Compounds for Improving mRNA Splicing

ABSTRACT

Provided herein are compounds useful for improving mRNA splicing in a cell. Exemplary compounds provided herein are useful for improving mRNA splicing in genes comprising at least one exon ending in the nucleotide sequence CAA. Methods for preparing the compounds and methods of treating diseases of the central nervous system are also provided.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/877,254, filed May 18, 2020, which is a continuation of U.S. patentapplication Ser. No. 15/543,826, filed on Jul. 14, 2017, now U.S. Pat.No. 10,676,475, which is a 371 U.S. National Phase Application ofPCT/US2016/013553, filed on Jan. 15, 2016, which claims the benefit ofU.S. Provisional Application Nos. 62/104,547, filed Jan. 16, 2015, and62/180,380, filed Jun. 16, 2015, the disclosures of each of which areincorporated herein by reference in their entirety.

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with Government support under Grant No.U01NS078025, awarded by the National Institutes of Health. TheGovernment has certain rights in the invention.

SEQUENCE LISTING

This application contains a Sequence Listing that has been submittedelectronically as an XML file named “40978-0010003_SL_ST26.XML.” The XMLfile, created on Mar. 27, 2023, is 32,980 bytes in size. The material inthe XML file is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present disclosure relates to compounds for treating disordersassociated with misspliced mRNA, and more particularly to kinetinderivatives for treating familial dysautonomia in a patient in needthereof.

BACKGROUND

Familial dysautonomia (FD) (MIM #2239001), also known as Riley Daysyndrome or hereditary sensory and autonomic neuropathy III (HSAN-III),is the best-known and most common member of a group of congenitalsensory and autonomic neuropathies (HSAN) characterized by widespreadsensory and variable autonomic dysfunction. FD affects neuronaldevelopment and is associated with progressive neuronal degeneration.Multiple systems are impacted resulting in a markedly reduced quality oflife and premature death. FD is caused by mutations in the IKBKAP geneand all cases described to date involve an intron 20 mutation thatresults in a unique pattern of tissue-specific exon skipping.

See also, for example, Shetty et al. Human Molecular Genetics, 2011,20(21):4093-4101; Axelrod et al. Pediatric Research, 2011,70(5):480-483; Gold-von Simson et al. Pediatric Research, 2009,65(3):341-346; Yoshida et al. PNAS, 2015, 112(9):2764-2769; andInternational Patent Application Nos. WO 2015/005491, WO 2010/118367,and WO 2014/124458, the disclosures of each of which are incorporated byreference herein in their entireties.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, can alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the disclosure which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable subcombination.

SUMMARY

The present application provides compounds of Formula (I):

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   X¹ is N or C;    -   X² is selected from the group consisting of S, N, NR², CR², and        CHR²;    -   X³ is selected from the group consisting of S, N, NR³, CR³, and        CHR³;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CHR⁴;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is absent or selected from the group consisting of C₁₋₆        alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, wherein the C₁₋₆        alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene are each        optionally substituted by 1, 2, 3, or 4 independently selected        R²⁰ groups;    -   R¹ is selected from the group consisting of a C₆₋₁₀ aryl,        2-benzofuranyl, 4-quinolinyl, a 5-6 member heteroaryl, and a 5-6        member heterocycloalkyl, each optionally substituted by 1, 2, 3,        or 4 independently selected R^(1A) groups;    -   each R^(1A) is independently selected from halo, CN, NO₂, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        —C(═O)OH, —C(═O)C₁₋₆ alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆        alkoxy;    -   R² is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a2), C(═O)R^(b2), C(═O)OR^(b2),        NR^(c2)R^(d2), C(═O)NR^(c2)R^(d2), —OC(═O)NR^(c2)R^(d2),        NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),        NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),        NR^(c2)S(═O)₂NR^(c2)R^(d2), S(O)NR^(c2)R^(d2), and        S(O)₂NR^(c2)R^(d2), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a3), SR^(a3), C(═O)R^(b3), C(═O)OR^(b3),        NR^(c3)R^(d3), C(═O)NR^(c3)R^(d3), —OC(═O)NR^(c3)R^(d3),        NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)OR^(b3),        NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)S(═O)₂R^(b3),        NR^(c3)S(═O)₂NR^(c3)R^(d3), S(O)NR^(c3)R^(d3), and        S(O)₂NR^(c3)R^(d3), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a4), C(═O)R^(b4), C(═O)OR^(b4),        NR^(c4)R^(d4), C(═O)NR^(c4)R^(d4), —OC(═O)NR^(c4)R^(d4),        NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4),        NR^(c4)C(═O)NR^(c4)R^(d4) NR^(c4)S(═O)₂R^(b4),        NR^(c4)S(═O)₂NR^(c4)R^(d4) S(O)NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)OR^(b5),        NR^(c5)R^(d5), C(═O)NR^(c5)R^(d5), —OC(═O)NR^(c5)R^(d5),        N^(c5)C(═O)R^(b5), NR^(c5)C(═O)OR^(b5),        NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),        NR^(c5)S(═O)₂NR^(c5)R^(d5), S(O)NR^(c5)R^(d5), and        S(O)₂NR^(c5)R^(d5), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁶ is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, and C₁₋₆ alkoxy;    -   R⁷ is selected from the group consisting of H, C₁₋₆ alkyl, CN,        NO₂, OR^(a7), C(═O)R^(b7), C(═O)OR^(b7), NR^(c7)R^(d7),        C(═O)NR^(c7)R^(d7), —OC(═O)NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7),        NR^(c7)C(═O)OR^(b7), NR^(c7)C(═O)NR^(c7)R^(d7),        NR^(c7)S(═O)₂R^(b7), and NR^(c7)S(═O)₂NR^(c7)R^(d7);    -   R⁸ is selected from the group consisting of H, C₁₋₆ alkyl, CN,        NO₂, OR^(a8), C(═O)R^(b8), C(═O)OR^(b8), NR^(c8)R^(d8),        C(═O)NR^(c8)R^(d8), —OC(═O)NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8),        NR^(c8)C(═O)OR^(b8), NR^(c8)C(═O)NR^(c8)R^(d8),        NR^(c8)S(═O)₂R^(b8), and NR^(c8)S(═O)₂NR^(c8)R^(d8);    -   each R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3),        R^(d3), R^(a4), R^(b4), R^(c4), R^(d4), R^(a5), R^(b5), R^(c5),        R^(d5), R^(a7), R^(b7), R^(c7), R^(d7), R^(a8), R^(b8), R^(c8),        and R^(d8) is independently selected from the group consisting        of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ hydroxyalkyl,        C₁₋₆ haloalkyl, C₁₋₆ alkoxy, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy, C₃₋₁₀        cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, —(C₁₋₆        alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, and 4-10 membered heterocycloalkyl are each        optionally substituted by 1, 2, 3, or 4 independently selected        R²⁰ groups;    -   or R^(c2) and R^(d2) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   or R^(c3) and R^(d3) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   or R^(c4) and R^(d4) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   each R²⁰ is independently selected from the group consisting of        OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl,        C₁₋₄ alkoxy, —(C₁₋₄ alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄        alkoxy), C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, carbamyl, C₁₋₄ alkylcarbamyl,        di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄        alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄        alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄        alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄        alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino;    -   wherein the ring comprising X¹, X², X³, and X⁴ forms a        cycloalkyl, heteroaryl or heterocycloalkyl ring;    -   with the proviso that when the 9-membered ring comprising X¹,        X², X³, X⁴, X⁷, and X⁸ forms Ring A:

-   -   then -L-R¹ does not form the following groups:

In some embodiments, X¹ is N. In some embodiments, X¹ is C.

In some embodiments, X² is N. In some embodiments, X² is NR². In someembodiments, X² is CR². In some embodiments, X² is CHR².

In some embodiments, X³ is N. In some embodiments, X³ is NR³. In someembodiments, X³ is CR³. In some embodiments, X³ is CHR³.

In some embodiments, X⁴ is S. In some embodiments, X⁴ is N. In someembodiments, X⁴ is NR⁴. In some embodiments, X⁴ is CR⁴. In someembodiments, X⁴ is CHR⁴.

In some embodiments, X⁷ is N. In some embodiments, X⁷ is CR⁷.

In some embodiments, X⁸ is N. In some embodiments, X⁸ is CR⁸.

In some embodiments, L is C₁₋₆ alkylene optionally substituted by 1, 2,3, or 4 independently selected R²⁰ groups. In some embodiments, L isunsubstituted C₁₋₆ alkylene. In some embodiments, L is unsubstitutedmethylene or unsubstituted ethylene.

In some embodiments, R¹ is selected from the group consisting of C₆₋₁₀aryl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(1A)groups. In some embodiments, R¹ is 2-benzofuranyl or 4-quinolinyl, eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(1A)groups. In some embodiments, R¹ is selected from the group consisting of2-benzofuranyl, 4-quinolinyl, phenyl, 5-6 membered heteroaryl, and 5-6membered heterocycloalkyl, each optionally substituted by 1 or 2independently selected R^(1A) groups. In some embodiments, R¹ isselected from the group consisting of 2-benzofuranyl, 4-quinolinyl, 5-6membered heteroaryl, and 5-6 membered heterocycloalkyl, each optionallysubstituted by 1 or 2 independently selected R^(1A) groups. In someembodiments, R¹ is selected from the group consisting of:

In some embodiments, each R^(1A) is independently selected from thegroup consisting of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,and —C(═O)OH. In some embodiments, each R^(1A) is independently selectedfrom the group consisting of CN, fluoro, chloro, methyl,trifluoromethyl, methoxy, and —C(═O)OH.

In some embodiments, R¹ is selected from the group consisting ofunsubstituted phenyl, unsubstituted 5-6 membered heteroaryl, andunsubstituted 5-6 membered heterocycloalkyl.

In some embodiments, R² is selected from the group consisting of H, oxo,halo, CN, C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl,5-6 membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups. In some embodiments, R² is selected from the group consisting ofH, oxo, chloro, fluoro, bromo, CN, methyl, —CH₂OH, —CH₂OCH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, NH₂, —NHCH₃, —N(CH₃)₂, phenyl, 4-pyridinyl, C(═O)OCH₃,C(═O)NH₂, C(═O)NHCH₃,

In some embodiments, R³ is selected from the group consisting of H, oxo,azido, CN, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 memberedheterocycloalkyl, are each optionally substituted by 1, 2, 3, or 4independently selected R²⁰ groups. In some embodiments, R³ is selectedfrom the group consisting of H, azido, CN, methyl, cyclopropyl,cyclobutyl, phenyl, 3-pyridinyl, N-morpholino, methoxy, ethoxy,n-propoxy, isopropoxy, n-butoxy, —OCH₂CH₂OH, —OCH₂CH₂CH₂OH,—OCH₂CH₂OCH₃, —OCH₂CH₂CH₂OCH₃, —ONHCH₃, —OCH₂CHF₂, —OCH₂CF₃,—OCH₂CH₂CF₃, —OCH₂CHF₂CH₃, —OCH₂CH₂NHC(═O)CH₃, cyclobutoxy,—OCH₂CH₂—O-phenyl, —SCH₃, —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—NHCH₂CH₂CH₂OH, —CH₂OCH₃, —CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂, —C(═O)OCH₃,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NHCH₂CH₂OH, —C(═O)NHCH₂CH₂OH,—OC(═O)CH₃, —OCH₂-azetidinyl, —OCH₂-oxetanyl,

In some embodiments, R⁴ is selected from the group consisting of H, oxo,azido, halo, CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R²⁰ groups. In some embodiments, R⁴ is selectedfrom the group consisting of H, halo, methyl, —CH₂CH₂F, —CH₂CH₂CF₃,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂C(═O)OH, —CH₂C(═O)NH(CH₃),—CH₂C(═O)N(CH₃)₂, —CH₂CH₂NHC(═O)CH₃, —CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂,

In some embodiments, R⁵ is selected from the group consisting of H,halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5),C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl. In someembodiments, R⁵ is selected from the group consisting of H, fluoro,chloro, bromo, iodo, CN, methyl, isopropyl, OH, OCH₃, NH₂, —NHCH₃,—N(CH₃)₂, —SCH₃, phenyl, cyclopropyl, and

In some embodiments, R⁵ is chloro or fluoro.

In some embodiments, R⁷ is selected from the group consisting of H, CN,and C(═O)NR^(c7)R^(d7).

In some embodiments, R⁷ is selected from the group consisting of H, CN,and C(═O)NH₂.

In some embodiments, R⁶ is H.

In some embodiments, R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is N, NR², CR², or CHR²;    -   X³ is N, NR³, CR³, or CHR³;    -   X⁴ is S, N, NR⁴, CR⁴, or CHR⁴;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted C₁₋₆ alkylene;    -   R¹ is selected from the group consisting of 2-benzofuranyl,        4-quinolinyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, 5-6 membered        heterocycloalkyl, optionally substituted by 1, 2, 3, or 4        independently selected R^(1A) groups;    -   each R^(1A) is independently selected from the group consisting        of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and        —C(═O)OH;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, are each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of 2-furanyl,        4-quinolinyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, and 5-6        membered heterocycloalkyl, optionally substituted by 1, 2, 3, or        4 independently selected R^(1A) groups;    -   each R^(1A) is independently selected from the group consisting        of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and        —C(═O)OH;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of 2-furanyl,        4-quinolinyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered        heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4        independently selected R^(1A) groups;    -   each R^(1A) is independently selected from the group consisting        of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and        —C(═O)OH;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of 2-furanyl,        4-quinolinyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered        heterocycloalkyl, each optionally substituted by 1 or 2        independently selected R^(1A) groups;    -   each R^(1A) is independently selected from the group consisting        of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and        —C(═O)OH;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of unsubstituted        2-furanyl, unsubstituted 4-quinolinyl, unsubstituted phenyl,        unsubstituted 5-6 membered heteroaryl;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of:

-   -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ia):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ib):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ic):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Id):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ie):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (If):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ig):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ih):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ij):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ik):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Im):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (In):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Io):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ip):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Iq):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ir):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Is):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (It):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is selected from thegroup of compounds provided in Table A, or a pharmaceutically acceptablesalt thereof.

The present application further provides a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of S, N, NR², CR², and        CHR²;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CHR⁴;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is absent or selected from the group consisting of C₁₋₆        alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, wherein the C₁₋₆        alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene are each        optionally substituted by 1, 2, 3, or 4 independently selected        R²⁰ groups;    -   R¹ is selected from the group consisting of a C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, and a 4-10 membered        heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4        independently selected R^(1A) groups;    -   each R^(1A) is independently selected from halo, CN, NO₂, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        —C(═O)OH, —C(═O)C₁₋₆ alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆        alkoxy;    -   R² is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a2), C(═O)R^(b2), C(═O)OR^(b2),        NR^(c2)R^(d2), C(═O)NR^(c2)R^(d2), —OC(═O)NR^(c2)R^(d2),        NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),        NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),        NR^(c2)S(═O)₂NR^(c2)R^(d2), S(O)NR^(c2)R^(d2), and        S(O)₂NR^(c2)R^(d2), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a4), C(═O)R^(b4), C(═O)OR^(b4),        NR^(c4)R^(d4), C(═O)NR^(c4)R^(d4), —OC(═O)NR^(c4)R^(d4),        NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4),        NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),        NR^(c4)S(═O)₂NR^(c4)R^(d4), S(O)NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)OR^(b5),        NR^(c5)R^(d5), C(═O)NR^(c5)R^(d5), —OC(═O)NR^(c5)R^(d5),        NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)OR^(b5),        NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),        NR^(c5)S(═O)₂NR^(c5)R^(d5), S(O)NR^(c5)R^(d5), and        S(O)₂NR^(c5)R^(d5), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁶ is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, and C₁₋₆ alkoxy, wherein the C₁₋₆        alkyl is optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R⁷ is selected from the group consisting of H, C₁₋₆ alkyl, CN,        NO₂, OR^(a7), C(═O)R^(b7), C(═O)OR^(b7), NR^(c7)R^(d7),        C(═O)NR^(c7)R^(d7), —OC(═O)NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7),        NR^(c7)C(═O)OR^(b7) NR^(c7)C(═O)NR^(c7)R^(d7)        NR^(c7)S(═O)₂R^(b7), and NR^(c7)S(═O)₂NR^(c7)R^(d7);    -   R⁸ is selected from the group consisting of H, C₁₋₆ alkyl, CN,        NO₂, OR^(a8), C(═O)R^(b8), C(═O)OR^(b8), NR^(c8)R^(d8),        C(═O)NR^(c8)R^(d8), —OC(═O)NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8),        NR^(c8)C(═O)OR^(b8), NR^(c8)C(═O)NR^(c8)R^(d8),        NR^(c8)S(═O)₂R^(b8), and NR^(c8)S(═O)₂NR^(c8)R^(d8);    -   R^(a3) is selected from the group consisting of H, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy,        —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₆₋₁₀ aryl, —(C₁₋₆        alkylene)-C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, —(C₁₋₆ alkylene)-(5-10        membered heteroaryl), 4-10 membered heterocycloalkyl, -(4-10        membered heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-10        membered heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆        alkyl)-NR^(3e)R^(3f), and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e),        wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, —(C₁₋₆ alkylene)-C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, —(C₁₋₆ alkylene)-(5-10 membered        heteroaryl), 4-10 membered heterocycloalkyl, and —(C₁₋₆        alkylene)-(4-10 membered heterocycloalkyl) are each optionally        substituted by 1, 2, 3, or 4 R²⁰ groups;    -   each R^(a2), R^(b2), R^(c2), R^(d2), R^(a4), R^(b4), R^(c4),        R^(d4), R^(a5), R^(b5), R^(c5), R^(d5), R^(a7), R^(b7), R^(c7),        R^(d7), R^(a8), R^(b8), R^(c8), and R^(d8) is independently        selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, —(C₁₋₆        alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, wherein the C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, —(C₁₋₆        alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, and 4-10 membered heterocycloalkyl are each        optionally substituted by 1, 2, 3, or 4 independently selected        R²⁰ groups;    -   or R^(c2) and R^(d2) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   or R^(c4) and R^(d4) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   each R^(3e) and R^(3f) is independently selected from the group        consisting of H and C₁₋₆ alkyl;    -   each R²⁰ is independently selected from the group consisting of        OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl,        C₁₋₄ alkoxy, —(C₁₋₄ alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄        alkoxy), C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, carbamyl, C₁₋₄ alkylcarbamyl,        di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄        alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄        alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄        alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄        alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino;    -   wherein the ring comprising X¹, X², and X⁴ forms a cycloalkyl,        heteroaryl or heterocycloalkyl ring.

In some embodiments, X¹ is N. In some embodiments, X¹ is C.

In some embodiments, X² is N. In some embodiments, X² is NR². In someembodiments, X² is CR². In some embodiments, X² is CHR².

In some embodiments, X⁴ is N. In some embodiments, X⁴ is NR⁴. In someembodiments, X⁴ is CR⁴. In some embodiments, X⁴ is CHR⁴.

In some embodiments, X⁷ is N. In some embodiments, X⁷ is CR⁷.

In some embodiments, X⁸ is N. In some embodiments, X⁸ is CR⁸.

In some embodiments, L is C₁₋₆ alkylene optionally substituted by 1, 2,3, or 4 independently selected R²⁰ groups. In some embodiments, L isunsubstituted C₁₋₆ alkylene. In some embodiments, L is unsubstitutedmethylene or unsubstituted ethylene.

In some embodiments, R¹ is selected from the group consisting of C₆₋₁₀aryl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(1A)groups. In some embodiments, R¹ is selected from the group consisting of5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(1A)groups. In some embodiments, R¹ is selected from the group consistingof:

In some embodiments, R¹ is selected from the group consisting of:

In some embodiments, R² is H or C₁₋₆ alkyl. In some embodiments, R² is Hor methyl.

In some embodiments, R⁴ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups. In some embodiments, R⁴ is H or —CH₂CH₂OH.

In some embodiments, R⁵ is selected from the group consisting of H,halo, CN, and OR^(a4). In some embodiments, R⁵ is selected from thegroup consisting of H, Cl, CN, and —OCH₃.

In some embodiments, R⁶ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups. In some embodiments, R⁶ is selected from the group consisting ofH, methyl, and —CH₂CH₂OH.

In some embodiments, R^(a3) is selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆alkoxy, —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₃₋₁₀ cycloalkyl, —(C₁₋₆alkylene)-C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-(5-10 membered heteroaryl),4-10 membered heterocycloalkyl, -(4-10 memberedheterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-10 memberedheterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆ alkyl)-NR^(3e)R^(3f), and—(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-(5-10membered heteroaryl), 4-10 membered heterocycloalkyl, and —(C₁₋₆alkylene)-(4-10 membered heterocycloalkyl) are each optionallysubstituted by 1, 2, 3, or 4 R²⁰ groups.

In some embodiments, R^(a3) is selected from the group consisting of H,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy, —(C₁₋₆alkylene)-C₆₋₁₀ aryloxy, C₆₋₁₀ aryl, —(C₁₋₆ alkylene)-C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,—(C₁₋₆ alkylene)-(5-10 membered heteroaryl), 4-10 memberedheterocycloalkyl, -(4-10 membered heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆alkylene)-(4-10 membered heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆alkyl)-NR^(3e)R^(3f), and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), whereinsaid C₁₋₆ alkyl, C₆₋₁₀ aryl, —(C₁₋₆ alkylene)-C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,—(C₁₋₆ alkylene)-(5-10 membered heteroaryl), 4-10 memberedheterocycloalkyl, and —(C₁₋₆ alkylene)-(4-10 membered heterocycloalkyl)are each optionally substituted by 1, 2, 3, or 4 R²⁰ groups.

In some embodiments, R^(a3) is selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆alkoxy, —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₆₋₁₀ aryl, —(C₁₋₆alkylene)-C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀cycloalkyl, 5-10 membered heteroaryl, —(C₁₋₆ alkylene)-(5-10 memberedheteroaryl), 4-10 membered heterocycloalkyl, -(4-10 memberedheterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-10 memberedheterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆ alkyl)-NR^(3e)R^(3f), and—(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), wherein said C₁₋₆ alkyl, C₆₋₁₀aryl, —(C₁₋₆ alkylene)-C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, —(C₁₋₆alkylene)-C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl, —(C₁₋₆alkylene)-(5-10 membered heteroaryl), 4-10 membered heterocycloalkyl,and —(C₁₋₆ alkylene)-(4-10 membered heterocycloalkyl) are eachoptionally substituted by 1, 2, 3, or 4 R²⁰ groups.

In some embodiments, R^(a3) is selected from the group consisting ofC₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy, —(C₁₋₆alkylene)-C₆₋₁₀ aryloxy, C₆₋₁₀ aryl, —(C₁₋₆ alkylene)-C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,—(C₁₋₆ alkylene)-(5-10 membered heteroaryl), 4-10 memberedheterocycloalkyl, -(4-10 membered heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆alkylene)-(4-10 membered heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆alkyl)-NR^(3e)R^(3f), and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), whereinsaid C₁₋₆ alkyl, C₆₋₁₀ aryl, —(C₁₋₆ alkylene)-C₆₋₁₀ aryl, C₃₋₁₀cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, 5-10 membered heteroaryl,—(C₁₋₆ alkylene)-(5-10 membered heteroaryl), 4-10 memberedheterocycloalkyl, and —(C₁₋₆ alkylene)-(4-10 membered heterocycloalkyl)are each optionally substituted by 1, 2, 3, or 4 R²⁰ groups.

In some embodiments, R^(a3) is selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆alkoxy, —(C₁₋₆ alkylene)-C₅₋₆ aryloxy, C₄₋₆ cycloalkyl, —(C₁₋₆alkylene)-C₄₋₆ cycloalkyl, —(C₁₋₆ alkylene)-(5-6 membered heteroaryl),4-6 membered heterocycloalkyl, -(4-6 memberedheterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-6 memberedheterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆ alkylene)-NR^(3e)R^(3f), and—(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), wherein the —(C₁₋₆ alkylene)-C₁₋₆alkoxy is substituted by phenyl.

In some embodiments, R^(a3) is selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CHF₂CH₃, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—NHCH₃, —CH₂CH₂NHC(═O)CH₃, cyclobutyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂CH₂—O-phenyl, azetidinyl, —CH₂-azetidinyl,oxetanyl, —CH₂-oxetanyl, —CH₂-thiazolyl,

In some embodiments:

-   -   X¹ is C;    -   X² is N or NR²;    -   X⁴ N or NR⁴;    -   X⁷ is N; and    -   X⁸ is N.

In some embodiments:

-   -   X¹ is C;    -   X² is N or NR²;    -   X⁴ N or NR⁴;    -   X⁷ is N;    -   X⁸ is N;    -   L is C₁₋₆ alkylene optionally substituted by 1, 2, 3, or 4        independently selected R²⁰ groups;    -   R¹ is selected from the group consisting of C₆₋₁₀ aryl, 5-6        membered heteroaryl, and 5-6 membered heterocycloalkyl, each        optionally substituted by 1, 2, 3, or 4 independently selected        R^(1A) groups;    -   each R^(1A) is independently selected from halo, CN, NO₂, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        —C(═O)OH, —C(═O)C₁₋₆ alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆        alkoxy;    -   R² is H or C₁₋₆ alkyl;    -   R^(a3) is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy,        —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₃₋₁₀ cycloalkyl, —(C₁₋₆        alkylene)-C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-(5-10 membered        heteroaryl), 4-10 membered heterocycloalkyl, -(4-10 membered        heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-10 membered        heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆ alkyl)-NR^(3e)R^(3f),        and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), wherein said C₁₋₆        alkyl, C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl,        —(C₁₋₆ alkylene)-(5-10 membered heteroaryl), 4-10 membered        heterocycloalkyl, and —(C₁₋₆ alkylene)-(4-10 membered        heterocycloalkyl) are each optionally substituted by 1, 2, 3, or        4 R²⁰ groups;    -   R⁴ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, and        OR^(a4);    -   R⁶ is H or C₁₋₆ alkyl;    -   each R^(3e) and R^(3f) is independently selected from the group        consisting of H and C₁₋₆ alkyl; and    -   each R²⁰ is independently selected from the group consisting of        OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl,        C₁₋₄ alkoxy, —(C₁₋₄ alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄        alkoxy), C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, carbamyl, C₁₋₄ alkylcarbamyl,        di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄        alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄        alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄        alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄        alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino.

In some embodiments:

-   -   X¹ is C;    -   X² is N or NR²;    -   X⁴ N or NR⁴;    -   X⁷ is N;    -   X⁸ is N;    -   L is unsubstituted C₁₋₆ alkylene;    -   R¹ is selected from the group consisting of 5-6 membered        heteroaryl, and 5-6 membered heterocycloalkyl, each optionally        substituted by 1, 2, 3, or 4 independently selected R^(1A)        groups;    -   each R^(1A) is independently selected from halo, CN, NO₂, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        —C(═O)OH, —C(═O)C₁₋₆ alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆        alkoxy;    -   R² is H or C₁₋₆ alkyl;    -   R⁴ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, and        OR^(a4);    -   R⁶ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   R^(a3) is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy,        —(C₁₋₆ alkylene)-C₅₋₆ aryloxy, C₄₋₆ cycloalkyl, —(C₁₋₆        alkylene)-C₄₋₆ cycloalkyl, —(C₁₋₆ alkylene)-(5-6 membered        heteroaryl), 4-6 membered heterocycloalkyl, -(4-6 membered        heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-6 membered        heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆        alkylene)-NR^(3e)R^(3f), and —(C₁₋₆        alkylene)-NR^(3e)C(═O)R^(4e), wherein the —(C₁₋₆ alkylene)-C₁₋₆        alkoxy is substituted by phenyl;    -   each R^(3e) and R^(3f) is independently selected from the group        consisting of H and C₁₋₆ alkyl; and    -   each R²⁰ is independently selected from the group consisting of        OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl,        C₁₋₄ alkoxy, —(C₁₋₄ alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄        alkoxy), C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, carbamyl, C₁₋₄ alkylcarbamyl,        di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄        alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄        alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄        alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄        alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino.

In some embodiments:

-   -   X¹ is C;    -   X² is N or NR²;    -   X⁴ is N or NR⁴;    -   X⁷ is N;    -   X⁸ is N;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of 5-6 membered        heteroaryl, and 5-6 membered heterocycloalkyl;    -   R² is H or C₁₋₆ alkyl;    -   R⁴ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1 R²⁰ group;    -   R⁵ is selected from the group consisting of H, halo, CN, and        OR^(a4);    -   R⁶ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1 R²⁰ group;    -   R^(a3) is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy,        —(C₁₋₆ alkylene)-C₅₋₆ aryloxy, C₄₋₆ cycloalkyl, —(C₁₋₆        alkylene)-C₄₋₆ cycloalkyl, —(C₁₋₆ alkylene)-(5-6 membered        heteroaryl), 4-6 membered heterocycloalkyl, -(4-6 membered        heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-6 membered        heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆        alkylene)-NR^(3e)R^(3f), and —(C₁₋₆        alkylene)-NR^(3e)C(═O)R^(4e), wherein the —(C₁₋₆ alkylene)-C₁₋₆        alkoxy is substituted by phenyl;    -   R^(a4) is C₁₋₆ alkyl;    -   each R^(3e) and R^(3f) is independently selected from the group        consisting of H and C₁₋₆ alkyl; and    -   each R²⁰ is OH.

In some embodiments, the compound of Formula (II) is a compound ofFormula (IIa):

or a pharmaceutically acceptable salt thereof,

-   -   wherein, R^(a3) is selected from the group consisting of H, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₁₋₆-hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆        alkoxy, —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₆₋₁₀-aryl, —(C₁₋₆        alkylene)-C₆₋₁₀ aryl, C₃₋₁₀-cycloalkyl,        —(C₁₋₆-alkylene)-C₃₋₁₀-cycloalkyl, 5-10 membered heteroaryl,        —(C₁₋₆ alkylene)-(5-10 membered heteroaryl), 4-10 membered        heterocycloalkyl, -(4-10 membered        heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-10 membered        heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆ alkyl)-NR^(3e)R^(3f),        and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), wherein said C₁₋₆        alkyl, C₆₋₁₀ aryl, —(C₁₋₆ alkylene)-C₆₋₁₀ aryl,        C₃₋₁₀-cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, —(C₁₋₆ alkylene)-(5-10 membered        heteroaryl), 4-10 membered heterocycloalkyl, and —(C₁₋₆        alkylene)-(4-10 membered heterocycloalkyl) are each optionally        substituted by 1, 2, 3, or 4 R²⁰ groups.

In some embodiments, the compound of Formula (II) is a compound ofFormula (IIb):

or a pharmaceutically acceptable salt thereof,

-   -   wherein, R^(a3) is selected from the group consisting of H, C₁₋₆        alkyl, C₁₋₆ haloalkyl, C₁₋₆-hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆        alkoxy, —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₆₋₁₀-aryl, —(C₁₋₆        alkylene)-C₆₋₁₀ aryl, C₃₋₁₀-cycloalkyl,        —(C₁₋₆-alkylene)-C₃₋₁₀-cycloalkyl, 5-10 membered heteroaryl,        —(C₁₋₆ alkylene)-(5-10 membered heteroaryl), 4-10 membered        heterocycloalkyl, -(4-10 membered        heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-10 membered        heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆ alkyl)-NR^(3e)R^(3f),        and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), wherein said C₁₋₆        alkyl, C₆₋₁₀ aryl, —(C₁₋₆ alkylene)-C₆₋₁₀ aryl,        C₃₋₁₀-cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, —(C₁₋₆ alkylene)-(5-10 membered        heteroaryl), 4-10 membered heterocycloalkyl, and —(C₁₋₆        alkylene)-(4-10 membered heterocycloalkyl) are each optionally        substituted by 1, 2, 3, or 4 R²⁰ groups.

In some embodiments, the compound of Formula (II) is selected from thegroup of compounds provided in Table B, or a pharmaceutically acceptablesalt thereof.

The present application further provides a pharmaceutical compositioncomprising a compound provided herein, or a pharmaceutically acceptablesalt thereof, and at least one pharmaceutically acceptable carrier.

The present application further provides a method of treating a diseaseassociated with one or more mRNA splicing defects in a subject in needthereof, the method comprising administering to the subject atherapeutically effective amount of a compound provided herein, or apharmaceutically acceptable salt thereof.

In some embodiments, the disease associated with one or more mRNAsplicing defects comprises a disease of the central nervous system. Insome embodiments, disease associated with one or more mRNA splicingdefects is a disease of the central nervous system. In some embodiments,the methods include delivering the compound to the central nervoussystem of a subject.

In some embodiments, the disease associated with one or more mRNAsplicing defects is selected from the group consisting of amyotrophiclateral sclerosis (ALS), atypical cystic fibrosis, autism, autismspectrum disorders, Charcot-Marie-Tooth disease, CHARGE syndrome,dementia, epilepsy, epileptic encephalopathy, familial dysautonomia(FD), familial isolated growth hormone deficiency type II (IGHD II),Frasier syndrome, frontotemporal dementia and Parkinson's linked toChromosome 17 (FTDP-17), Huntington's disease, Marfan syndrome, mentalretardation, Menkes Disease (MD), muscular dystrophies, myopathies,myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2),neurofibromatosis 1 (NF1, von Recklinghausen NF; peripheral NF),occipital horn syndrome, Parkinson's disease, retinoblastoma,schizophrenia, tuberous sclerosis, and the gene-associated diseaseslisted in Table 1. In some embodiments, the disease associated with oneor more mRNA splicing defects is selected from the group consisting offamilial dysautonomia and neurofibromatosis 1. In some embodiments, thedisease associated with one or more mRNA splicing defects is familialdysautonomia. In some embodiments, the disease associated with one ormore mRNA splicing defects is neurofibromatosis 1. In some embodiments,the disease associated with one or more mRNA splicing defects is adisease listed in Table 1.

In some embodiments, the one or more mRNA splicing defects is associatedwith one or more genes comprising at least one exon comprising thenucleotide sequence CAA. In some embodiments, the one or more mRNAsplicing defects is associated with one gene comprising at least oneexon comprising the nucleotide sequence CAA. In some embodiments, theone or more mRNA splicing defects is associated with one or more genesselected from the group consisting of BMP2K, ABI2, IKBKAP, FIG4, DNAJC6,WDR45, LRRK2, LRSAM1, SBF2, C19orf12, ARFGEF2, ARHGEF6, CC2D2A, CHD8,CUL4B, KDM5C, MBD5, OPHN1, PGAP1, SLC9A9, SLC35A3, CACNA1S, CDKL5, FMR1,HDAC8, MECP2, SLC6A8, SYNGAP1, CHD2, CHRNA4, DEPDC5, GOSR2, GRIN2A,SCN1A, SCN9A, STXBP1, SZT2, DMD, COL6A3, DYNC2H1, FKTN, IGHMBP2, LAMA2,MTM1, NEB, PLEC, MICU1, SMCHD1, DES, RYR1, TSC1, TSC2, FBN1, RB1, andCHD7.

In some embodiments, the one or more mRNA splicing defects is associatedwith one gene selected from the group consisting of BMP2K, ABI2, IKBKAP,FIG4, DNAJC6, WDR45, LRRK2, LRSAM1, SBF2, C19orf12, ARFGEF2, ARHGEF6,CC2D2A, CHD8, CUL4B, KDM5C, MBD5, OPHN1, PGAP1, SLC9A9, SLC35A3,CACNA1S, CDKL5, FMR1, HDAC8, MECP2, SLC6A8, SYNGAP1, CHD2, CHRNA4,DEPDC5, GOSR2, GRIN2A, SCN1A, SCN9A, STXBP1, SZT2, DMD, COL6A3, DYNC2H1,FKTN, IGHMBP2, LAMA2, MTM1, NEB, PLEC, MICU1, SMCHD1, DES, RYR1, TSC1,TSC2, FBN1, RB1, and CHD7. In some embodiments, the one or more genes isselected from the group provided in Table 1. In some embodiments, thegene is selected from the group provided in Table 1. In someembodiments, the gene is associated with a condition listed in Table 1as associated with a gene provided therein.

The present application further provides, a method of improving mRNAsplicing of a gene (e.g., a gene in a cell), comprising contacting acell expressing the gene with a compound provided herein, or apharmaceutically acceptable salt thereof. In some embodiments, the geneis selected from the group consisting of BMP2K, ABI2, IKBKAP, FIG4,DNAJC6, WDR45, LRRK2, LRSAM1, SBF2, C19orf12, ARFGEF2, ARHGEF6, CC2D2A,CHD8, CUL4B, KDM5C, MBD5, OPHN1, PGAP1, SLC9A9, SLC35A3, CACNA1S, CDKL5,FMR1, HDAC8, MECP2, SLC6A8, SYNGAP1, CHD2, CHRNA4, DEPDC5, GOSR2,GRIN2A, SCN1A, SCN9A, STXBP1, SZT2, DMD, COL6A3, DYNC2H1, FKTN, IGHMBP2,LAMA2, MTM1, NEB, PLEC, MICU1, SMCHD1, DES, RYR1, TSC1, TSC2, FBN1, RB1,and CHD7. In some embodiments, the gene is selected from the groupprovided in Table 1. In some embodiments, the contacting the cell isperformed in vitro. In some embodiments, the contacting the cell isperformed in vivo. In some embodiments, the method of improving mRNAsplicing in a gene comprises improving exon inclusion.

The present application further provides a method of improving mRNAsplicing in a cell, comprising contacting the cell with an effectiveamount of a compound provided herein, or a pharmaceutically acceptablesalt thereof, wherein the improving comprises improving mRNA splicing ina gene.

The present application further provides a method of improving mRNAsplicing in a cell, comprising contacting the cell with a compoundprovided herein, or a pharmaceutically acceptable salt thereof, whereinthe improving comprises improving mRNA splicing in a gene selected fromthe group consisting of BMP2K, ABI2, IKBKAP, FIG4, DNAJC6, WDR45, LRRK2,LRSAM1, SBF2, C19orf12, ARFGEF2, ARHGEF6, CC2D2A, CHD8, CUL4B, KDM5C,MBD5, OPHN1, PGAP1, SLC9A9, SLC35A3, CACNA1S, CDKL5, FMR1, HDAC8, MECP2,SLC6A8, SYNGAP1, CHD2, CHRNA4, DEPDC5, GOSR2, GRIN2A, SCN1A, SCN9A,STXBP1, SZT2, DMD, COL6A3, DYNC2H1, FKTN, IGHMBP2, LAMA2, MTM1, NEB,PLEC, MICU1, SMCHD1, DES, RYR1, TSC1, TSC2, FBN1, RB1, and CHD7. In someembodiments, the gene is selected from the group provided in Table 1. Insome embodiments, the contacting the cell is performed in vitro. In someembodiments, the contacting the cell is performed in vivo. In someembodiments, the method of improving mRNA splicing in a gene comprisesimproving exon inclusion.

In some embodiments, the methods described herein can include assayingmRNA splicing in a cell in the presence of a compound as providedherein, and detecting an improvement in mRNA splicing (e.g., increasingthe rate of exon inclusion) in the cell.

In some embodiments, the methods described herein are practiced on acell or a subject who has a genetic mutation that causes an mRNAsplicing defect, i.e., impaired or abnormal mRNA splicing that differsfrom mRNA splicing in a wild-type cell. The methods can includeidentifying a subject who has such a genetic mutation and/or identifyinga subject who has a condition associated with an mRNA splicing defect asdescribed herein or known in the art.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

DESCRIPTION OF DRAWINGS

FIG. 1A shows percent exon 20 inclusion in C57BI6-FD mouse liver afteradministration of compound (100) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day; and administration of kinetin at 400 mg/kg/day.

FIG. 1B shows percent exon 20 inclusion in C57BI6-FD mouse liver afteradministration of compound (230) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day.

FIG. 1C shows percent exon 20 inclusion in C57BI6-FD mouse liver afteradministration of compound (270) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day.

FIG. 2A shows percent exon 20 inclusion in C57BI6-FD mouse heart afteradministration of compound (100) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day; and administration of kinetin at 400 mg/kg/day.

FIG. 2B shows percent exon 20 inclusion in C57BI6-FD mouse heart afteradministration of compound (230) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day.

FIG. 2C shows percent exon 20 inclusion in C57BI6-FD mouse heart afteradministration of compound (270) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day.

FIG. 3A shows percent exon 20 inclusion in C57BI6-FD mouse kidney afteradministration of compound (100) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day; and administration of kinetin at 400 mg/kg/day.

FIG. 3B shows percent exon 20 inclusion in C57BI6-FD mouse kidney afteradministration of compound (230) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day.

FIG. 3C shows percent exon 20 inclusion in C57BI6-FD mouse kidney afteradministration of compound (270) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day.

FIG. 4A shows percent exon 20 inclusion in C57BI6-FD mouse brain afteradministration of compound (100) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day; and administration of kinetin at 400 mg/kg/day.

FIG. 4B shows percent exon 20 inclusion in C57BI6-FD mouse brain afteradministration of compound (230) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day.

FIG. 4C shows percent exon 20 inclusion in C57BI6-FD mouse brain afteradministration of compound (270) at 10 mg/kg/day; 30 mg/kg/day; and 60mg/kg/day.

FIG. 5 shows percent exon 20 inclusion in C57BI6-FD mouse trigeminalnerve after administration of compound (270) at 10 mg/kg/day; 30mg/kg/day; and 60 mg/kg/day.

FIG. 6 shows percent exon 20 inclusion in C57BI6-FD mouse sciatic nerveafter administration of compound (270) at 10 mg/kg/day; 30 mg/kg/day;and 60 mg/kg/day.

FIG. 7 shows results of a Western Blot on familial dysautonomia (FD)human fibroblast treated for five days with representative compounds(230), (302), (270), and (100).

DETAILED DESCRIPTION

Mutations that alter mRNA splicing have been estimated to account for asmany as 20-30% of all disease-causing mutations, and studies havedemonstrated that alternatively spliced isoforms are highly prevalent inthe brain. These data collectively suggest that defects in alternativesplicing may be a driver of neurodegenerative disease. Oraladministration of kinetin (N⁶-furfuryladenine) in mice (400 mg/kg/dayfor 7 days) has been shown to improve IKBKAP splicing in vivo in certaintissues, including the brain. Further, preliminary testing in humanpatients and carriers of familial dysautonomia led to increased normalIKBKAP mRNA in peripheral blood in humans (see e.g., U.S. Pat. Nos.8,729,025 and 7,737,110, the disclosures of which are each incorporatedby reference herein in their entireties). However, high doses werenecessary to achieve splicing changes. Accordingly, the presentapplication provides compounds useful for therapeutically targeting mRNAsplicing mechanisms.

The present application provides compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of S, N, NR², CR², and        CHR²;    -   X³ is selected from the group consisting of S, N, NR³, CR³, and        CHR³;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CHR⁴;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is absent or selected from the group consisting of C₁₋₆        alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, wherein the C₁₋₆        alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene are each        optionally substituted by 1, 2, 3, or 4 independently selected        R²⁰ groups;    -   R¹ is selected from the group consisting of a C₆₋₁₀ aryl,        2-benzofuranyl, 4-quinolinyl, a 5-6 member heteroaryl, and a 5-6        member heterocycloalkyl, each optionally substituted by 1, 2, 3,        or 4 independently selected R^(1A) groups;    -   each R^(1A) is independently selected from halo, CN, NO₂, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        —C(═O)OH, —C(═O)C₁₋₆ alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆        alkoxy;    -   R² is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a2), C(═O)R^(b2), C(═O)OR^(b2),        NR^(c2)R^(d2), C(═O)NR^(c2)R^(d2), —OC(═O)NR^(c2)R^(d2),        NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),        NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),        NR^(c2)S(═O)₂NR^(c2)R^(d2), S(O)NR^(c2)R^(d2), and        S(O)₂NR^(c2)R^(d2), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a3), SR^(a3), C(═O)R^(b3), C(═O)OR^(b3),        NR^(c3)R^(d3), C(═O)NR^(c3)R^(d3), —OC(═O)NR^(c3)R^(d3),        NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)OR^(b3),        NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)S(═O)₂R^(b3),        NR^(c3)S(═O)₂NR^(c3)R^(d3), S(O)NR^(c3)R^(d3), and        S(O)₂NR^(c3)R^(d3), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a4), C(═O)R^(b4), C(═O)OR^(b4),        NR^(c4)R^(d4), C(═O)NR^(c4)R^(d4), —OC(═O)NR^(c4)R^(d4),        NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4),        NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),        NR^(c4)S(═O)₂NR^(c4)R^(d4), S(O)NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)OR^(b5),        NR^(c5)R^(d5), C(═O)NR^(c5)R^(d5), —OC(═O)NR^(c5)R^(d5),        NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)OR^(b5),        NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),        NR^(c5)S(═O)₂NR^(c5)R^(d5), S(O)NR^(c5)R^(d5), and        S(O)₂NR^(c5)R^(d5), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁶ is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, and C₁₋₆ alkoxy;    -   R⁷ is selected from the group consisting of H, C₁₋₆ alkyl, CN,        NO₂, OR^(a7), C(═O)R^(b7), C(═O)OR^(b7), NR^(c7)R^(d7),        C(═O)NR^(c7)R^(d7), —OC(═O)NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7),        NR^(c7)C(═O)OR^(b7) NR^(c7)C(═O)NR^(c7)R^(d7)        NR^(c7)S(═O)₂R^(b7), and NR^(c7)S(═O)₂NR^(c7)R^(d7);    -   R⁸ is selected from the group consisting of H, C₁₋₆ alkyl, CN,        NO₂, OR^(a8), C(═O)R^(b8), C(═O)OR^(b8), NR^(c8)R^(d8),        C(═O)NR^(c8)R^(d8), —OC(═O)NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8),        NR^(c8)C(═O)OR^(b8), NR^(c8)C(═O)NR^(c8)R^(d8),        NR^(c8)S(═O)₂R^(b8), and NR^(c8)S(═O)₂NR^(c8)R^(d8);    -   each R^(a2), R^(b2), R^(c2), R^(d2), R^(a3), R^(b3), R^(c3),        R^(d3), R^(a4), R^(b4), R^(c4), R^(d4), R^(a5), R^(b5), R^(c5),        R^(d5), R^(a7), R^(b7), R^(c7), R^(d7), R^(a8), R^(b8), R^(C8),        and R^(d8) is independently selected from the group consisting        of H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ hydroxyalkyl,        C₁₋₆ haloalkyl, C₁₋₆ alkoxy, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy, C₃₋₁₀        cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10        membered heteroaryl, 4-10 membered heterocycloalkyl, wherein the        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, —(C₁₋₆        alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, and 4-10 membered heterocycloalkyl are each        optionally substituted by 1, 2, 3, or 4 independently selected        R²⁰ groups;    -   or R^(c2) and R^(d2) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   or R^(c3) and R^(d3) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   or R^(c4) and R^(d4) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   each R²⁰ is independently selected from the group consisting of        OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl,        C₁₋₄ alkoxy, —(C₁₋₄ alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄        alkoxy), C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, carbamyl, C₁₋₄ alkylcarbamyl,        di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄        alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄        alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄        alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄        alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino;    -   wherein the ring comprising X¹, X², X³, and X⁴ forms a        cycloalkyl, heteroaryl or heterocycloalkyl ring;    -   with the proviso that when the 9-membered ring comprising X¹,        X², X³, X⁴, X⁷, and X⁸ forms Ring A:

then -L-R¹ does not form the following groups:

In some embodiments, X¹ is N. In some embodiments, X¹ is C.

In some embodiments, X² is S. In some embodiments, wherein X² is N. Insome embodiments, X² is NR². In some embodiments, X² is CR². In someembodiments, is CHR².

In some embodiments, X³ is S. In some embodiments, X³ is N. In someembodiments, X³ is NR³. In some embodiments, X³ is CR³. In someembodiments, X³ is CHR³.

In some embodiments, X⁴ is S. In some embodiments, X⁴ is N. In someembodiments, X⁴ is NR⁴. In some embodiments, X⁴ is CR⁴. In someembodiments, is CHR⁴.

In some embodiments, X⁷ is N. In some embodiments, X⁷ is CR⁷.

In some embodiments, X⁸ is N. In some embodiments, X⁸ is CR⁸. In someembodiments, X⁸ is CH.

In some embodiments, L is C₁₋₆ alkylene optionally substituted by 1, 2,3, or 4 independently selected R²⁰ groups. In some embodiments, L isunsubstituted C₁₋₆ alkylene. In some embodiments, L is unsubstitutedmethylene or unsubstituted ethylene.

In some embodiments, R¹ is selected from the group consisting of C₆₋₁₀aryl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(1A)groups. In some embodiments, R¹ is 2-benzofuranyl or 4-quinolinyl, eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(1A)groups. In some embodiments, R¹ is selected from the group consisting of2-benzofuranyl, 4-quinolinyl, phenyl, 5-6 membered heteroaryl, and 5-6membered heterocycloalkyl, each optionally substituted by 1 or 2independently selected R^(1A) groups. In some embodiments, R¹ isselected from the group consisting of unsubstituted phenyl,unsubstituted 5-6 membered heteroaryl, and unsubstituted 5-6 memberedheterocycloalkyl. In some embodiments, R¹ is selected from the groupconsisting of 2-benzofuranyl, 4-quinolinyl, 5-6 membered heteroaryl, and5-6 membered heterocycloalkyl, each optionally substituted by 1 or 2independently selected R^(1A) groups. In some embodiments, R¹ isselected from the group consisting of:

In some embodiments, each R^(1A) is independently selected from thegroup consisting of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,and —C(═O)OH. In some embodiments, each R^(1A) is independently selectedfrom the group consisting of CN, fluoro, chloro, methyl,trifluoromethyl, methoxy, and —C(═O)OH.

In some embodiments, R² is selected from the group consisting of H, oxo,halo, CN, C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl,5-6 membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups. In some embodiments, R² is selected from the group consisting ofH, oxo, chloro, fluoro, bromo, CN, methyl, —CH₂OH, —CH₂OCH₃, —CH₂NHCH₃,—CH₂N(CH₃)₂, NH₂, —NHCH₃, —N(CH₃)₂, phenyl, 4-pyridinyl, C(═O)OCH₃,C(═O)NH₂, C(═O)NHCH₃,

In some embodiments, R³ is selected from the group consisting of H, oxo,azido, CN, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,5-6 membered heterocycloalkyl, OR^(a8), SR^(a3), NR^(c3)R^(d3),C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 memberedheterocycloalkyl, are each optionally substituted by 1, 2, 3, or 4independently selected R²⁰ groups. In some embodiments, R³ is —OR^(a3).In some embodiments, R³ is selected from the group consisting of H,azido, CN, methyl, cyclopropyl, cyclobutyl, phenyl, 3-pyridinyl,N-morpholino, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,—OCH₂CH₂OH, —OCH₂CH₂CH₂OH, —OCH₂CH₂OCH₃, —OCH₂CH₂CH₂OCH₃, —ONHCH₃,—OCH₂CHF₂, —OCH₂CF₃, —OCH₂CH₂CF₃, —OCH₂CHF₂CH₃, —OCH₂CH₂NHC(═O)CH₃,cyclobutoxy, —OCH₂CH₂—O-phenyl, —SCH₃, —NH₂, —NHCH₃, —NHCH₂CH₃,—N(CH₃)₂, —NHCH₂CH₂CH₂OH, —CH₂OCH₃, —CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂,—C(═O)OCH₃, —C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NHCH₂CH₂OH,—C(═O)NHCH₂CH₂OH, —OC(═O)CH₃, —OCH₂-azetidinyl, —OCH₂-oxetanyl,

In some embodiments, R⁴ is selected from the group consisting of H, oxo,azido, halo, CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R²⁰ groups. In some embodiments, R⁴ is selectedfrom the group consisting of H, halo, methyl, —CH₂CH₂F, —CH₂CH₂CF₃,—CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂OCH₃, —CH₂C(═O)OH, —CH₂C(═O)NH(CH₃),—CH₂C(═O)N(CH₃)₂, —CH₂CH₂NHC(═O)CH₃, —CH₂CH₂NHCH₃, —CH₂CH₂N(CH₃)₂,

In some embodiments, R⁵ is selected from the group consisting of H,halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5),C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl. In someembodiments, R⁵ is selected from the group consisting of H, fluoro,chloro, bromo, iodo, CN, methyl, isopropyl, OH, OCH₃, NH₂, —NHCH₃,—N(CH₃)₂, —SCH₃, phenyl, cyclopropyl, and

In some embodiments, R⁵ is chloro or fluoro. In some embodiments, R⁵ ischloro. In some embodiments, R⁵ is fluoro.

In some embodiments, R⁶ is H or C₁₋₆ alkyl. In some embodiments, R⁶ isH. In some embodiments, R⁶ is C₁₋₆ alkyl. In some embodiments, R⁶ isC₁₋₆ haloalkyl. In some embodiments, R⁶ is C₁₋₆ hydroxyalkyl. In someembodiments, R⁶ is C₁₋₆ alkoxy.

In some embodiments, R⁷ is selected from the group consisting of H, CN,and C(═O)NR^(c7)R^(d7). In some embodiments, R⁷ is selected from thegroup consisting of H, CN, and C(═O)NH₂.

In some embodiments, R⁸ is H or C₁₋₆ alkyl. In some embodiments, R⁸ isH.

In some embodiments:

-   -   X¹ is N or C;    -   X² is N, NR², CR², or CHR²;    -   X³ is N, NR³, CR³, or CHR³;    -   X⁴ is S, N, NR⁴, CR⁴, or CHR⁴;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted C₁₋₆ alkylene;    -   R¹ is selected from the group consisting of 2-benzofuranyl,        4-quinolinyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, 5-6 membered        heterocycloalkyl, optionally substituted by 1, 2, 3, or 4        independently selected R^(1A) groups;    -   each R^(1A) is independently selected from the group consisting        of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and        —C(═O)OH;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, are each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of 2-furanyl,        4-quinolinyl, C₆₋₁₀ aryl, 5-6 membered heteroaryl, and 5-6        membered heterocycloalkyl, optionally substituted by 1, 2, 3, or        4 independently selected R^(1A) groups;    -   each R^(1A) is independently selected from the group consisting        of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and        —C(═O)OH;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of 2-furanyl,        4-quinolinyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered        heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4        independently selected R^(1A) groups;    -   each R^(1A) is independently selected from the group consisting        of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and        —C(═O)OH;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of 2-furanyl,        4-quinolinyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered        heterocycloalkyl, each optionally substituted by 1 or 2        independently selected R^(1A) groups;    -   each R^(1A) is independently selected from the group consisting        of halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and        —C(═O)OH;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of unsubstituted        2-furanyl, unsubstituted 4-quinolinyl, unsubstituted phenyl,        unsubstituted 5-6 membered heteroaryl;    -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of N, NR², CR², and        CH₂;    -   X³ is selected from the group consisting of N, NR³, CR³, and        CH₂;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CH₂;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of:

-   -   R² is selected from the group consisting of H, oxo, halo, CN,        C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6        membered heterocycloalkyl, C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2),        wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are        each optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R³ is selected from the group consisting of H, oxo, azido, CN,        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3),        C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the        C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl,        5-6 membered heterocycloalkyl are each optionally substituted by        1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, C₁₋₆ alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered        heterocycloalkyl, wherein the C₁₋₆ alkyl and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, C₁₋₆        alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆        cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl;    -   R⁶ is H;    -   R⁷ is selected from the group consisting of H, CN, and        C(═O)NR^(c7)R^(d7); and    -   R⁸ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R³, R⁴, R⁵, R⁶ of Formula (Ia) are defined        according to the definitions described herein for compounds of        Formula (I).

In some embodiments, L is absent or selected from the group consistingof an unsubstituted C₁₋₆ alkylene, an unsubstituted C₂₋₆ alkenylene, anda C₂₋₆ alkynylene. In some embodiments, L is selected from the groupconsisting of an unsubstituted C₁₋₆ alkylene, an unsubstituted C₂₋₆alkenylene, and a C₂₋₆ alkynylene. In some embodiments, L is anunsubstituted C₁₋₆ alkylene. In some embodiments, L is an unsubstitutedmethylene or an unsubstituted ethylene. In some embodiments, L is anunsubstituted methylene.

In some embodiments, R¹ is a 5-6 membered heteroaryl or a 5-6 memberedheterocycloalkyl, each optionally substituted by 1, 2, 3, or 4independently selected R^(1A) groups. In some embodiments, R¹ is a 5-6membered heteroaryl optionally substituted by 1, 2, 3, or 4independently selected R^(1A) groups. In some embodiments, R¹ is anunsubstituted 5-6 membered heteroaryl or an unsubstituted 5-6 memberedheterocycloalkyl. In some embodiments, R¹ is an unsubstituted 5-6membered heteroaryl.

In some embodiments, R², R³, and R⁴ are each independently selected fromH and C₁₋₆ alkyl. In some embodiments, R², R³, and R⁴ are each H.

In some embodiments, R⁵ is selected from the group consisting of H andhalo. In some embodiments, R⁵ is halo. In some embodiments, R⁵ is chloroor fluoro. In some embodiments, R⁵ is chloro.

In some embodiments, R⁶ is H or C₁₋₆ alkyl. In some embodiments, R⁶ isH.

In some embodiments, the compound of Formula (Ia) is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ib):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R⁴, R⁵, and R⁶ of Formula (Ib) are defined        according to the definitions described herein for compounds of        Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ic):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R³, R⁴, R⁵, and R⁶ of Formula (Ic) are defined        according to the definitions described herein for compounds of        Formula (I). In some embodiments, R⁶ is H. In some embodiments,        R³ is —OR^(a3).

In some embodiments, the compound of Formula (I) is a compound ofFormula (Id):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R³, R⁴, R⁵, R⁶ of Formula (Id) are defined        according to the definitions described herein for compounds of        Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ie):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R³, R⁵, and R⁶ of Formula (Ie) are defined        according to the definitions described herein for compounds of        Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (If):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R³, R⁴, R⁵, and R⁶ of Formula (If) are        defined according to the definitions described herein for        compounds of Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ig):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R³, R⁵, R⁶ and R⁷ of Formula (Ig) are        defined according to the definitions described herein for        compounds of Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ih):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R³, R⁵, R⁶ of Formula (Ih) are defined        according to the definitions described herein for compounds of        Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ij):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R⁴, R⁵, and R⁶ of Formula (Ij) are defined        according to the definitions described herein for compounds of        Formula (I).

In some embodiments, L is absent or selected from the group consistingof an unsubstituted C₁₋₆ alkylene, an unsubstituted C₂₋₆ alkenylene, anda C₂₋₆ alkynylene. In some embodiments, L is selected from the groupconsisting of an unsubstituted C₁₋₆ alkylene, an unsubstituted C₂₋₆alkenylene, and a C₂₋₆ alkynylene. In some embodiments, L is anunsubstituted C₁₋₆ alkylene. In some embodiments, L is an unsubstitutedmethylene or an unsubstituted ethylene. In some embodiments, L is anunsubstituted methylene.

In some embodiments, R¹ is a 5-6 membered heteroaryl or a 5-6 memberedheterocycloalkyl, each optionally substituted by 1, 2, 3, or 4independently selected R^(1A) groups. In some embodiments, R¹ is a 5-6membered heteroaryl optionally substituted by 1, 2, 3, or 4independently selected R^(1A) groups. In some embodiments, R¹ is anunsubstituted 5-6 membered heteroaryl or an unsubstituted 5-6 memberedheterocycloalkyl. In some embodiments, R¹ is an unsubstituted 5-6membered heteroaryl.

In some embodiments, R¹ is an unsubstituted 5-membered heteroaryl.

In some embodiments, R⁵ is H or halo. In some embodiments, R⁵ is halo.In some embodiments, R⁵ is chloro or fluoro. In some embodiments, R⁵ ischloro.

In some embodiments, R⁶ is H or C₁₋₆ alkyl. In some embodiments, R⁶ isH.

In some embodiments, the compound of Formula (Ij) is:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ik):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R³, R⁵, R⁶, and R⁷ of Formula (Ik) are defined        according to the definitions described herein for compounds of        Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Im):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R³, R⁴, R⁵, R⁶, and R⁷ of Formula (Im) are        defined according to the definitions described herein for        compounds of Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (In):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R³, R⁴, R⁵, and R⁶ of Formula (In) are        defined according to the definitions described herein for        compounds of Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Io):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R³, R⁴, R⁵, R⁶, and R⁷ of Formula (Io) are        defined according to the definitions described herein for        compounds of Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ip):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R³, R⁴, R⁵, and R⁶ of Formula (Ip) are        defined according to the definitions described herein for        compounds of Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Iq):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R³, R⁴, R⁵, R⁶, and R⁷ of Formula (Iq) are        defined according to the definitions described herein for        compounds of Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Ir):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R³, R⁵, and R⁶ of Formula (Ir) are defined        according to the definitions described herein for compounds of        Formula (I). In some embodiments, R⁶ is H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (Is):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R³, R⁴, R⁵, R⁶, and R⁸ of Formula (Is) are        defined according to the definitions described herein for        compounds of Formula (I). In some embodiments, R⁶ is H. In some        embodiments, R⁸ is H. In some embodiments, R⁶ and R⁸ are each H.

In some embodiments, the compound of Formula (I) is a compound ofFormula (It):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   variables L, R¹, R², R³, R⁴, R⁵, R⁶ of Formula (It) are defined        according to the definitions described herein for compounds of        Formula (I). In some embodiments, R⁶ is H. In some embodiments,        R⁸ is H. In some embodiments, R⁶ and R⁸ are each H.

In some embodiments, the compound of Formula (I) is selected from thegroup of compounds provided in Table A, or a pharmaceutically acceptablesalt thereof.

TABLE A

(1)

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

(10)

(11)

(12)

(13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

(24)

(25)

(26)

(27)

(28)

(29)

(30)

(31)

(32)

(33)

(34)

(35)

(36)

(37)

(38)

(39)

(40)

(41)

(42)

(43)

(44)

(45)

(46)

(47)

(48)

(49)

(50)

(51)

(52)

(53)

(54)

(55)

(56)

(57)

(58)

(59)

(60)

(61)

(62)

(63)

(64)

(65)

(66)

(67)

(68)

(69)

(70)

(71)

(72)

(73)

(74)

(75)

(76)

(77)

(78)

(79)

(80)

(81)

(82)

(83)

(84)

(85)

(86)

(87)

(88)

(89)

(90)

(91)

(92)

(93)

(94)

(95)

(96)

(97)

(98)

(99)

(100)

(101)

(102)

(103)

(104)

(105)

(106)

(107)

(108)

(109)

(110)

(111)

(112)

(113)

(114)

(115)

(116)

(117)

(118)

(119)

(120)

(121)

(122)

(123)

(124)

(125)

(126)

(127)

(128)

(129)

(130)

(131)

(132)

(133)

(134)

(135)

(136)

(137)

(138)

(139)

(140)

(141)

(142)

(143)

(144)

(145)

(146)

(147)

(148)

(149)

(150)

(151)

(152)

(153)

(154)

(155)

(156)

(157)

(158)

(159)

(160)

(161)

(162)

(163)

(164)

(165)

(166)

(167)

(168)

(169)

(170)

(171)

(172)

(173)

(174)

(175)

(176)

(177)

(178)

(179)

(180)

(181)

(182)

(183)

(184)

(185)

(186)

(187)

(188)

(189)

(190)

(191)

(192)

(193)

(194)

(195)

(196)

(197)

(198)

(199)

(200)

(201)

(202)

(203)

(204)

(205)

(206)

(207)

(208)

(209)

(210)

(211)

(212)

(213)

(214)

(215)

(216)

(217)

(218)

(219)

(220)

(221)

(222)

(223)

(224)

(225)

(226)

(227)

(228)

(229)

(230)

(231)

(232)

(233)

(234)

(235)

(236)

(237)

(238)

(239)

(240)

(241)

(242)

(243)

(244)

(245)

(246)

(247)

(248)

(249)

(250)

(251)

(252)

(253)

(254)

(255)

(256)

(257)

(258)

(259)

(260)

(261)

(262)

(263)

(264)

(265)

(266)

(267)

(268)

(269)

(270)

(271)

(272)

(273)

(274)

(275)

(276)

(277)

(278)

(279)

(280)

(281)

(282)

(283)

(284)

(285)

(286)

(287)

(288)

(289)

(290)

(291)

(292)

(293)

(294)

(295)

(296)

(297)

(298)

(299)

(300)

(301)

(302)

(303)

(304)

(305)

(306)

(307)

(308)

(309)

(310)

(311)

(312)

(313)

(314)

(315)

(316)

(317)

(318)

(319)

(320)

(321)

(322)

(323)

(324)

(325)

(326)

(327)

(328)

(329)

(330)

(331)

(332)

(333)

(334)

(335)

(336)

(337)

(338)

(339)

(340)

(341)

(342)

(343)

(344)

(346)

(347)

(348)

(349)

(350)

(351)

(352)

(353)

(354)

(355)

(356)

(357)

(358)

(359)

(360)

(361)

(362)

(363)

(364)

(365)

(366)

(367)

(368)

(369)

(370)

(371)

(372)

(373)

(374)

(375)

(376)

(377)

(378)

(379)

(380)

(381)

(382)

(383)

(384)

(385)

(386)

(387)

(388)

(389)

(390)

(391)

(392)

(393)

(394)

(395)

(396)

(397)

(398)

(399)

(400)

(401)

(402)

(465)

(466)

(467)

(468)

(469)

(470)

(471)

(472)

(473)

(474)

(475)

(476)

(477)

(478)

(479)

(480)

(481)

(482)

(483)

(484)

(485)

(486)

(487)

(488)

(489)

(490)

(491)

(492)

(493)

(494)

(495)

(496)

(497)

(498)

(499)

(500)

(501)

(502)

(503)

(504)

(505)

(506)

(507)

(508)

(509)

(510) and

(511)

In some embodiments, the compound of Formula (I) is selected from thegroup of compounds provided in Table A-2, or a pharmaceuticallyacceptable salt thereof.

TABLE A-2

(302)

(230)

(271)

(269)

(270)

(275)

(274)

(107)

(100)

(285)

(468)

In some embodiments, the compound of Formula (I) is selected from thegroup of compounds provided in Table A-3, or a pharmaceuticallyacceptable salt thereof.

TABLE A-3

(302)

(270)

(230)

(271)

The present application further provides compounds of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

-   -   X¹ is N or C;    -   X² is selected from the group consisting of S, N, NR², CR², and        CR²;    -   X⁴ is selected from the group consisting of S, N, NR⁴, CR⁴, and        CHR⁴;    -   X⁷ is N or CR⁷;    -   X⁸ is N or CR⁸;    -   L is absent or selected from the group consisting of C₁₋₆        alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, wherein the C₁₋₆        alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene are each        optionally substituted by 1, 2, 3, or 4 independently selected        R²⁰ groups;    -   R¹ is selected from the group consisting of a C₆₋₁₀ aryl, C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, and a 4-10 membered        heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4        independently selected R^(1A) groups;    -   each R^(1A) is independently selected from halo, CN, NO₂, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        —C(═O)OH, —C(═O)C₁₋₆ alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆        alkoxy;    -   R² is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a2), C(═O)R^(b2), C(═O)OR^(b2),        NR^(c2)R^(d2), C(═O)NR^(c2)R^(d2), —OC(═O)NR^(c2)R^(d2),        NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2),        NR^(c2)C(═O)NR^(c2)R^(d2), NR^(c2)S(═O)₂R^(b2),        NR^(c2)S(═O)₂NR^(c2)R^(d2), S(O)NR^(c2)R^(d2), and        S(O)₂NR^(c2)R^(d2), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁴ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a4), C(═O)R^(b4), C(═O)OR^(b4),        NR^(c4)R^(d4), C(═O)NR^(c4)R^(d4), —OC(═O)NR^(c4)R^(d4),        NR^(c4)C(═O)R^(b4), NR^(c4)C(═O)OR^(b4),        NR^(c4)C(═O)NR^(c4)R^(d4), NR^(c4)S(═O)₂R^(b4),        NR^(c4)S(═O)₂NR^(c4)R^(d4), S(O)NR^(c4)R^(d4), and        S(O)₂NR^(c4)R^(d4), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, oxo, azido, halo,        CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀        cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 membered        heterocycloalkyl, OR^(a5), SR^(a5), C(═O)R^(b5), C(═O)OR^(b5),        NR^(c5)R^(d5), C(═O)NR^(c5)R^(d5), —OC(═O)NR^(c5)R^(d5),        NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)OR^(b5),        NR^(c5)C(═O)NR^(c5)R^(d5), NR^(c5)S(═O)₂R^(b5),        NR^(c5)S(═O)₂NR^(c5)R^(d5), S(O)NR^(c5)R^(d5), and        S(O)₂NR^(c5)R^(d5), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl,        C₆₋₁₀ aryl, 5-10 membered heteroaryl, and 4-10 membered        heterocycloalkyl are each optionally substituted by 1, 2, 3, or        4 independently selected R²⁰ groups;    -   R⁶ is selected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, and C₁₋₆ alkoxy, wherein the C₁₋₆        alkyl is optionally substituted by 1, 2, 3, or 4 independently        selected R²⁰ groups;    -   R⁷ is selected from the group consisting of H, C₁₋₆ alkyl, CN,        NO₂, OR^(a7), C(═O)R^(b7), C(═O)OR^(b7), NR^(c7)R^(d7),        C(═O)NR^(c7)R^(d7), —OC(═O)NR^(c7)R^(d7), NR^(c7)C(═O)R^(b7),        NR^(c7)C(═O)OR^(b7), NR^(c7)C(═O)NR^(c7)R^(d7),        NR^(c7)S(═O)₂R^(b7), and NR^(c7)S(═O)₂NR^(c7)R^(d7);    -   R⁸ is selected from the group consisting of H, C₁₋₆ alkyl, CN,        NO₂, OR^(a8), C(═O)R^(b8), C(═O)OR^(b8), NR^(c8)R^(d8),        C(═O)NR^(c8)R^(d8), —OC(═O)NR^(c8)R^(d8), NR^(c8)C(═O)R^(b8),        NR^(c8)C(═O)OR^(b8), NR^(c8)C(═O)NR^(c8)R^(d8),        NR^(c8)S(═O)₂R^(b8), and NR^(c8)S(═O)₂NR^(c8)R^(d8);    -   R^(a3) is selected from the group consisting of H, C₁₋₆ alkyl,        C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy,        —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₆₋₁₀ aryl, —(C₁₋₆        alkylene)-C₆₋₁₀ aryl, C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀        cycloalkyl, 5-10 membered heteroaryl, —(C₁₋₆ alkylene)-(5-10        membered heteroaryl), 4-10 membered heterocycloalkyl, -(4-10        membered heterocycloalkyl)-C(═O)OR³, —(C₁₋₆ alkylene)-(4-10        membered heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆        alkyl)-NR^(3e)R^(3f), and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e),        wherein said C₁₋₆ alkyl, C₆₋₁₀ aryl, —(C₁₋₆ alkylene)-C₆₋₁₀        aryl, C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, 5-10        membered heteroaryl, —(C₁₋₆ alkylene)-(5-10 membered        heteroaryl), 4-10 membered heterocycloalkyl, and —(C₁₋₆        alkylene)-(4-10 membered heterocycloalkyl) are each optionally        substituted by 1, 2, 3, or 4 R²⁰ groups;    -   each R^(a2), R^(b2), R^(c2), R^(d2), R^(a4), R^(b4), R^(c4),        R^(d4), R^(a5), R^(b5), R^(c5), R^(d5), R^(a7), R^(b7), R^(c7),        R^(d7), R^(a8), R^(b8), R^(c8), and R^(d8) is independently        selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆        alkoxy, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, —(C₁₋₆        alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, 4-10 membered heterocycloalkyl, wherein the C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, —(C₁₋₆        alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 membered        heteroaryl, and 4-10 membered heterocycloalkyl are each        optionally substituted by 1, 2, 3, or 4 independently selected        R²⁰ groups;    -   or R^(c2) and R^(d2) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   or R^(c4) and R^(d4) together with the N atom to which they are        connected, come together to form a 5-10 membered heteroaryl or        4-10 membered heterocycloalkyl ring, each optionally substituted        by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   each R^(3e) and R^(3f) is independently selected from the group        consisting of H and C₁₋₆ alkyl;    -   each R²⁰ is independently selected from the group consisting of        OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl,        C₁₋₄ alkoxy, —(C₁₋₄ alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄        alkoxy), C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, carbamyl, C₁₋₄ alkylcarbamyl,        di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄        alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄        alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄        alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄        alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino;    -   wherein the ring comprising X¹, X², and X⁴ forms a cycloalkyl,        heteroaryl or heterocycloalkyl ring.

In some embodiments, X¹ is N. In some embodiments, X¹ is C.

In some embodiments, X² is N. In some embodiments, X² is NR². In someembodiments, X² is CR². In some embodiments, X² is CHR². In someembodiments, X² is S.

In some embodiments, X⁴ is N. In some embodiments, X⁴ is NR⁴. In someembodiments, X⁴ is CR⁴. In some embodiments, X⁴ is CHR⁴. In someembodiments, X⁴ is S.

In some embodiments, X⁷ is N. In some embodiments, X⁷ is CR⁷.

In some embodiments, X⁸ is N. In some embodiments, X⁸ is CR⁸.

In some embodiments, L is C₁₋₆ alkylene optionally substituted by 1, 2,3, or 4 independently selected R²⁰ groups. In some embodiments, L isunsubstituted C₁₋₆ alkylene. In some embodiments, L is unsubstitutedmethylene or unsubstituted ethylene.

In some embodiments, R¹ is selected from the group consisting of C₆₋₁₀aryl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(1A)groups. In some embodiments, R¹ is selected from the group consisting of5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, eachoptionally substituted by 1, 2, 3, or 4 independently selected R^(1A)groups.

In some embodiments, R¹ is selected from the group consisting of:

In some embodiments, R¹ is selected from the group consisting of:

In some embodiments, R² is H or C₁₋₆ alkyl. In some embodiments, R² is Hor methyl.

In some embodiments, R⁴ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups. In some embodiments, R⁴ is H or —CH₂CH₂OH.

In some embodiments, R⁵ is selected from the group consisting of H,halo, CN, and OR^(a4). In some embodiments, R⁵ is selected from thegroup consisting of H, Cl, CN, and —OCH₃.

In some embodiments, R⁶ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl isoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups. In some embodiments, R⁶ is selected from the group consisting ofH, methyl, and —CH₂CH₂OH.

In some embodiments, R^(a3) is selected from the group consisting ofC₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆alkoxy, —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₃₋₁₀ cycloalkyl, —(C₁₋₆alkylene)-C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-(5-10 membered heteroaryl),4-10 membered heterocycloalkyl, -(4-10 memberedheterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-10 memberedheterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆ alkyl)-NR^(3e)R^(3f), and—(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), wherein said C₁₋₆ alkyl, C₃₋₁₀cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-(5-10membered heteroaryl), 4-10 membered heterocycloalkyl, and —(C₁₋₆alkylene)-(4-10 membered heterocycloalkyl) are each optionallysubstituted by 1, 2, 3, or 4 R²⁰ groups. In some embodiments, R^(a3) isselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy, —(C₁₋₆ alkylene)-C₅₋₆aryloxy, C₄₋₆ cycloalkyl, —(C₁₋₆ alkylene)-C₄₋₆ cycloalkyl, —(C₁₋₆alkylene)-(5-6 membered heteroaryl), 4-6 membered heterocycloalkyl,-(4-6 membered heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-6membered heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆alkylene)-NR^(3e)R^(3f), and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e),wherein the —(C₁₋₆ alkylene)-C₁₋₆ alkoxy is substituted by phenyl. Insome embodiments, R^(a3) is selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, n-butyl, —CH₂CH₂OH, —CH₂CH₂CH₂OH,—CH₂CHF₂, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CHF₂CH₃, —CH₂CH₂OCH₃, —CH₂CH₂CH₂OCH₃,—NHCH₃, —CH₂CH₂NHC(═O)CH₃, cyclobutyl, —CH₂-cyclobutyl,—CH₂-cyclopentyl, —CH₂CH₂—O-phenyl, azetidinyl, —CH₂-azetidinyl,oxetanyl, —CH₂-oxetanyl, —CH₂-thiazolyl,

In some embodiments:

-   -   X¹ is C;    -   X² is N or NR²;    -   X⁴ N or NR⁴;    -   X⁷ is N; and    -   X⁸ is N.

In some embodiments:

-   -   X¹ is C;    -   X² is N or NR²;    -   X⁴ N or NR⁴;    -   X⁷ is N;    -   X⁸ is N;    -   L is C₁₋₆ alkylene optionally substituted by 1, 2, 3, or 4        independently selected R²⁰ groups;    -   R¹ is selected from the group consisting of C₆₋₁₀ aryl, 5-6        membered heteroaryl, and 5-6 membered heterocycloalkyl, each        optionally substituted by 1, 2, 3, or 4 independently selected        R^(1A) groups;    -   each R^(1A) is independently selected from halo, CN, NO₂, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        —C(═O)OH, —C(═O)C₁₋₆ alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆        alkoxy;    -   R² is H or C₁₋₆ alkyl;    -   R^(a3) is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy,        —(C₁₋₆ alkylene)-C₆₋₁₀ aryloxy, C₃₋₁₀ cycloalkyl, —(C₁₋₆        alkylene)-C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-(5-10 membered        heteroaryl), 4-10 membered heterocycloalkyl, -(4-10 membered        heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-10 membered        heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆ alkyl)-NR^(3e)R^(3f),        and —(C₁₋₆ alkylene)-NR^(3e)C(═O)R^(4e), wherein said C₁₋₆        alkyl, C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl,        —(C₁₋₆ alkylene)-(5-10 membered heteroaryl), 4-10 membered        heterocycloalkyl, and —(C₁₋₆ alkylene)-(4-10 membered        heterocycloalkyl) are each optionally substituted by 1, 2, 3, or        4 R²⁰ groups;    -   R⁴ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, and        OR^(a4);    -   R⁶ is H or C₁₋₆ alkyl;    -   each R^(3e) and R^(3f) is independently selected from the group        consisting of H and C₁₋₆ alkyl; and    -   each R²⁰ is independently selected from the group consisting of        OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl,        C₁₋₄ alkoxy, —(C₁₋₄ alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄        alkoxy), C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, carbamyl, C₁₋₄ alkylcarbamyl,        di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄        alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄        alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄        alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄        alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino.

In some embodiments:

-   -   X¹ is C;    -   X² is N or NR²;    -   X⁴ N or NR⁴;    -   X⁷ is N;    -   X⁸ is N;    -   L is unsubstituted C₁₋₆ alkylene;    -   R¹ is selected from the group consisting of 5-6 membered        heteroaryl, and 5-6 membered heterocycloalkyl, each optionally        substituted by 1, 2, 3, or 4 independently selected R^(1A)        groups;    -   each R^(1A) is independently selected from halo, CN, NO₂, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,        —C(═O)OH, —C(═O)C₁₋₆ alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆        alkoxy;    -   R² is H or C₁₋₆ alkyl;    -   R⁴ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   R⁵ is selected from the group consisting of H, halo, CN, and        OR^(a4);    -   R⁶ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1, 2, 3, or 4 independently selected R²⁰ groups;    -   R^(a3) is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy,        —(C₁₋₆ alkylene)-C₅₋₆ aryloxy, C₄₋₆ cycloalkyl, —(C₁₋₆        alkylene)-C₄₋₆ cycloalkyl, —(C₁₋₆ alkylene)-(5-6 membered        heteroaryl), 4-6 membered heterocycloalkyl, -(4-6 membered        heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-6 membered        heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆        alkylene)-NR^(3e)R^(3f), and —(C₁₋₆        alkylene)-NR^(3e)C(═O)R^(4e), wherein the —(C₁₋₆ alkylene)-C₁₋₆        alkoxy is substituted by phenyl;    -   each R^(3e) and R^(3f) is independently selected from the group        consisting of H and C₁₋₆ alkyl; and    -   each R²⁰ is independently selected from the group consisting of        OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄        alkynyl, C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl,        C₁₋₄ alkoxy, —(C₁₋₄ alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄        alkoxy), C₁₋₄ haloalkoxy, C₃₋₆ cycloalkyl, phenyl, 5-6 membered        heteroaryl, 5-6 membered heterocycloalkyl, amino, C₁₋₄        alkylamino, di(C₁₋₄ alkyl)amino, carbamyl, C₁₋₄ alkylcarbamyl,        di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄ alkylcarbamoyl, di(C₁₋₄        alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄ alkoxycarbonyl, C₁₋₄        alkylcarbonylamino, C₁₋₄ alkylsulfonylamino, aminosulfonyl, C₁₋₄        alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,        aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄        alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄        alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino.

In some embodiments:

-   -   X¹ is C;    -   X² is N or NR²;    -   X⁴ is N or NR⁴;    -   X⁷ is N;    -   X⁸ is N;    -   L is unsubstituted methylene or unsubstituted ethylene;    -   R¹ is selected from the group consisting of 5-6 membered        heteroaryl, and 5-6 membered heterocycloalkyl;    -   R² is H or C₁₋₆ alkyl;    -   R⁴ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1 R²⁰ group;    -   R⁵ is selected from the group consisting of H, halo, CN, and        OR^(a4);    -   R⁶ is H or C₁₋₆ alkyl, wherein the C₁₋₆ alkyl is optionally        substituted by 1 R²⁰ group;    -   R^(a3) is selected from the group consisting of C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₁₋₆ hydroxyalkyl, —(C₁₋₆ alkylene)-C₁₋₆ alkoxy,        —(C₁₋₆ alkylene)-C₅₋₆ aryloxy, C₄₋₆ cycloalkyl, —(C₁₋₆        alkylene)-C₄₋₆ cycloalkyl, —(C₁₋₆ alkylene)-(5-6 membered        heteroaryl), 4-6 membered heterocycloalkyl, -(4-6 membered        heterocycloalkyl)-C(═O)OR^(3f), —(C₁₋₆ alkylene)-(4-6 membered        heterocycloalkyl), —NR^(3e)R^(3f), —(C₁₋₆        alkylene)-NR^(3e)R^(3f), and —(C₁₋₆        alkylene)-NR^(3e)C(═O)R^(4e), wherein the —(C₁₋₆ alkylene)-C₁₋₆        alkoxy is substituted by phenyl;    -   R^(a4) is C₁₋₆ alkyl;    -   each R^(3e) and R^(3f) is independently selected from the group        consisting of H and C₁₋₆ alkyl; and    -   each R²⁰ is OH.

In some embodiments, the compound of Formula (II) is a compound ofFormula (IIa):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is a compound ofFormula (IIb):

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula (II) is selected from thegroup of compounds provided in Table B, or a pharmaceutically acceptablesalt thereof.

TABLE B

(2)

(124)

(184)

(230)

(233)

(239)

(249)

(259)

(260)

(261)

(265)

(267)

(269)

(270)

(271)

(272)

(273)

(274)

(275)

(276)

(277)

(278)

(280)

(282)

(287)

(289)

(290)

(291)

(292)

(293)

(294)

(296)

(297)

(299)

(300)

(302)

(305)

(306)

(307)

(308)

(309)

(310)

(311)

(312)

(315)

(317)

(318)

(319)

(320)

(321)

(324)

(326)

(327)

(328)

(329)

(331)

(332)

(333)

(334)

(335)

(336)

(337)

(338)

(339)

(340)

(341)

(346)

(347)

(348)

(349)

(351)

(362)

(365)

(370)

(374)

(375)

(376)

(382)

(384)

(385)

(386)

(387)

(388)

(389)

(390)

(391)

(392)

(393)

(394)

(395)

(396)

(397)

(398)

(399)

(400)

(401)

(402)

(468)

(469)

(471)

(472)

(473)

(474)

(475)

(476)

(477)

(478)

(479)

(480)

(481)

(482)

(483)

(484)

(485)

(486)

(488)

(489)

(490)

(491)

(492)

(493)

(496)

(497)

(499)

(500)

(504)

(505)

(506)

(507)

(511)

In some embodiments, the compound of Formula (II) is selected from thegroup of compounds provided in Table B-2, or a pharmaceuticallyacceptable salt thereof.

TABLE B-2

(302)

(230)

(271)

(269)

(270)

(275)

(274)

In some embodiments, the compound of Formula (II) is selected from thegroup of compounds provided in Table B-3, or a pharmaceuticallyacceptable salt thereof.

TABLE B-3

(302)

(270)

(230)

(271)

In some embodiments, the compound of Formula (I) or the compound ofFormula (II) is not a compound provided in Table C.

TABLE C

(403)

(404)

(405)

(406)

(407)

(408)

(409)

(410)

(411)

(412)

(413)

(414)

(415)

(416)

(417)

(418)

(419)

(420)

(421)

(422)

(423)

(424)

(425)

(426)

(427)

(428)

(429)

(430)

(431)

(432)

(433)

(434)

(435)

(436)

(437)

(438)

(439)

(440)

(441)

(442)

(443)

(444)

(445)

(446)

(447)

(448)

(449)

(450)

(451)

(452)

(453)

(454)

(455)

(456)

(457)

(458)

(459)

(460)

(461)

(462)

(463)

(464)

(512)

General Definitions

The following abbreviations may be used herein: ADME (Absorption,Distribution, Metabolism, and Excretion); aq. (aqueous); n-BuOH(n-butanol); calc. (calculated); d (doublet); dd (doublet of doublets);DBTCE (dibromotetrachloroethane); DCM (dichloromethane); DIPEA(N,N-diisopropylethylamine); DMA (dimethylacetamide); DMEM (Dulbecco'sModified Eagle's Media); DMF (N,N-dimethylformamide); eq. or equiv.(equivalents); Et (ethyl); EtOAc (ethyl acetate); EtOH (ethanol); FD(familial dysautonomia); g (gram(s)); h (hour(s)); HPLC (highperformance liquid chromatography); Hz (hertz); IPA (isopropyl alcohol);J (coupling constant); KOH (potassium hydroxide); LCMS (liquidchromatography-mass spectrometry); LDA (lithium diisopropylamide); m(multiplet); M (molar); Me (methyl); MeI (methyl iodide); MeCN(acetonitrile); MeOH (methanol); mg (milligram(s)); min. (minutes(s));mL (milliliter(s)); mmol (millimole(s)); MS (Mass spectrometry); Na₂SO₄(sodium sulfate); nM (nanomolar); NMR (nuclear magnetic resonancespectroscopy); PBS (phosphate buffered saline); t (triplet or tertiary);TEA (triethylamine); THF (tetrahydrofuran); TLC (thin layerchromatography); μg (microgram(s)); μL (microliter(s)); μM (micromolar);wt % (weight percent).

Synthesis

As will be appreciated, the compounds provided herein, including saltsthereof, can be prepared using known organic synthesis techniques andcan be synthesized according to any of numerous possible syntheticroutes.

The compounds of Formula (I) and Formula (II) can be prepared, forexample, using a process as illustrated in Scheme I. A mixture of thedesired chloropyrrolopyrimidine or purine i-A, desired aminomethylheterocycle or appropriately substituted aryl or benzyl amine ii-A, andamine base (e.g. triethylamine or diisopropylethylamine) in anappropriate solvent (e.g., 1,4-dioxane) are stirred at 50-150° C. in asealed tube to afford a compound iii-A.

The compounds of Formula (I) can also be prepared, for example,according to the procedure illustrated in Scheme II. A mixture of thedesired chloropyrazolopyrimidine i-B, desired aminomethyl heterocycle orappropriately substituted aryl or benzyl amine ii-B, and amine base(e.g., triethylamine or diisopropylethylamine) in an appropriate solvent(e.g., 1,4-dioxane) are stirred at 50-150° C. in a sealed tube to affordthe desired product iii-B.

The compounds of Formula (I) can also be prepared, for example,according to the procedure illustrated in Scheme III. A mixture of5,6-diaminouracil sulfate salt i-C, the desired carboxylic acid or acidchloride ii-C, POCl₃, and NH₄Cl are stirred at 100° C. until thereaction is complete by LC-MS and/or TLC analysis. The reaction mixtureis cooled to room temperature and carefully poured over ice. Subsequentneutralization of the reaction solution and purification using standardtechniques affords the desired compound iii-C. A mixture of the desiredchloropurine iv-C, desired aminomethyl heterocycle or appropriatelysubstituted aryl or benzyl amine iv-C (1.1 equiv), and amine base (e.g.,triethylamine or diisopropylethylamine) in an appropriate solvent (e.g.1,4-dioxane) are stirred at 50-150° C. in a sealed tube to afford thedesired product v-C.

The compounds of Formula (I) and Formula (II) can also be prepared, forexample, according to the procedure illustrated in Scheme IV.2,6-Dichloropurine i-D, dihydropyran, and para-toluenesulfonic acid inan appropriate solvent (e.g., ethyl acetate) are stirred at 65° C.overnight. After this time, the reaction is cooled to room temperatureand washed with saturated basic solution (e.g., NaHCO₃ solution)followed by brine. The solution was dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford a clear residue. Theresulting residue is then triturated with an appropriate alcoholicsolvent (e.g., MeOH) to afford ii-D.

To a solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineii-D in an appropriate solvent (e.g., THF) is added LDA (3 equiv) at−78° C. and stirred for about 20 to about 40 minutes. After this time, asolution of dibromotetrachloroethane in an appropriate solvent (e.g.,THF) is added slowly and stirred at −78° C. for about 90 to about 120minutes to afford the title compound iii-D.

8-Bromo-2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine is reactedwith an appropriately substituted heterocyclic, aryl, or benzyl amine(e.g., 2-(aminomethyl)thiazole dihydrochloride, 4-(aminomethyl)pyridine,4-(aminomethyl)pyrimidine hydrochloride, or furfurylamine) in thepresence of an amine base (e.g., trimethylamine) in an appropriatesolvent (e.g., 1,4-dioxane) to afford the desired compound of iv-D. Thecompound iv-D is then reacted with an appropriate substituted alkylalcohol in the presence of a base (e.g., potassium tert-butoxide, sodiumhydride, or sodium hydroxide) at about 60 to about 90° C. to afford thedesired compound v-D.

Lastly, the THP protected alkoxy purine v-D in an appropriate solvent(e.g., MeOH) is treated with excess strong acid (e.g. trifluoroaceticacid) at 0° C. Upon addition of the TFA, the reaction mixture is stirredand heated at about 40° C. to about 55° C. until the reaction iscomplete by LC-MS and/or TLC analysis. Subsequent purification affordsthe desired compound vi-D. The product structure was confirmed by ¹H NMRand/or by mass analysis.

The compounds of Formula (I) and Formula (II) can also be prepared, forexample, according to the procedure illustrated in Scheme V. A mixtureof compound i-E and the desired amine ii-E is stirred at about 40° C. toabout 60° C. until the reaction is complete by LC-MS and/or TLCanalysis. Subsequent purification affords the desired compound iii-E. Toa solution of THP protected amino purine iii-E in an appropriate solvent(e.g., MeOH) is added an excess of strong acid (e.g., trifluoroaceticacid) at 0° C. Upon addition of the acid, the reaction mixture isstirred and heated to about 65° C. until the reaction is complete byLC-MS and/or TLC analysis. Subsequent purification affords the desiredcompound iii-E.

The compounds of Formula (I) can also be prepared, for example,according to the procedure illustrated in Scheme VI. A mixture of thedesired chlorothiazolopyrimidines i-F, desired aminomethyl heterocycleor appropriately substituted aryl or benzylamine ii-F, and amine base(e.g., trimethylamine) in an appropriate solvent (e.g., 1,4-dioxane) isstirred at room temperature until the reaction was complete by LC-MSand/or TLC analysis. Subsequent purification affords the desiredcompound iii-F.

The compounds of Formula (I) and Formula (II) can also be prepared, forexample, according to the procedure illustrated in Scheme VII. A mixtureof the desired chlorotriazolopyrimidines i-G, desired aminomethylheterocycle or appropriately substituted aryl or benzylamine ii-G, andamine base (e.g., triethylamine) in an appropriate solvent (e.g.,1,4-dioxane) is stirred at room temperature until the reaction iscomplete by LC-MS and/or TLC analysis. Subsequent purification affordsthe desired product iii-G.

The compounds of Formula (I) and Formula (II) can also be prepared, forexample, according to the procedure illustrated in Scheme VIII. Amixture of the desired chloroimidazopyrimidines i-H, desired aminomethylheterocycle or appropriately substituted aryl or benzylamine ii-H, andamine base (e.g., triethylamine) in an appropriate solvent (e.g.1,4-dioxane) is stirred at about 70° C. until the reaction is completeby LC-MS and/or TLC analysis. Subsequent purification afford the desiredproduct iii-H.

The compounds of Formula (I) and Formula (II) can also be prepared, forexample, according to the procedure illustrated in Scheme IX. A mixtureof the dichloroimidazopyrimidines i-J, desired aminomethyl heterocyclei-J, and amine base (e.g., trimethylamine) in an appropriate solvent(e.g., 1,4-dioxane) is stirred at about 55° C. until the reaction iscomplete by LC-MS and/or TLC analysis. Subsequent purification affordsthe desired product iii-J.

It will be appreciated by one skilled in the art that the processesdescribed herein are not the exclusive means by which compounds providedherein may be synthesized and that a broad repertoire of syntheticorganic reactions is available to be potentially employed insynthesizing compounds provided herein. The person skilled in the artknows how to select and implement appropriate synthetic routes. Suitablesynthetic methods of starting materials, intermediates and products maybe identified by reference to the literature, including referencesources such as: Advances in Heterocyclic Chemistry, Vols. 1-107(Elsevier, 1963-2012); Journal of Heterocyclic Chemistry Vols. 1-49(Journal of Heterocyclic Chemistry, 1964-2012); Carreira, et al. (Ed.)Science of Synthesis, Vols. 1-48 (2001-2010) and Knowledge UpdatesKU2010/1-4; 2011/1-4; 2012/1-2 (Thieme, 2001-2012); Katritzky, et al.(Ed.) Comprehensive Organic Functional Group Transformations, (PergamonPress, 1996); Katritzky et al. (Ed.); Comprehensive Organic FunctionalGroup Transformations II (Elsevier, 2^(nd) Edition, 2004); Katritzky etal. (Ed.), Comprehensive Heterocyclic Chemistry (Pergamon Press, 1984);Katritzky et al., Comprehensive Heterocyclic Chemistry II, (PergamonPress, 1996); Smith et al., March's Advanced Organic Chemistry:Reactions, Mechanisms, and Structure, 6^(th) Ed. (Wiley, 2007); Trost etal. (Ed.), Comprehensive Organic Synthesis (Pergamon Press, 1991).

The reactions for preparing compounds described herein can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynon-reactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,(e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature). A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected by the skilled artisan.

Preparation of compounds described herein can involve the protection anddeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups, can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3^(rd) Ed., Wiley &Sons, Inc., New York (1999).

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or¹³C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), massspectrometry, or by chromatographic methods such as high performanceliquid chromatography (HPLC), liquid chromatography-mass spectroscopy(LCMS), or thin layer chromatography (TLC). Compounds can be purified bythose skilled in the art by a variety of methods, including highperformance liquid chromatography (HPLC) and normal phase silicachromatography.

At various places in the present specification, divalent linkingsubstituents are described. It is specifically intended that eachdivalent linking substituent include both the forward and backward formsof the linking substituent. For example, —NR(CR′R″)_(n)— includes both—NR(CR′R″)_(n)— and —(CR′R″)_(n)NR—. Where the structure clearlyrequires a linking group, the Markush variables listed for that groupare understood to be linking groups.

The term “n-membered” where n is an integer typically describes thenumber of ring-forming atoms in a moiety where the number ofring-forming atoms is n. For example, piperidinyl is an example of a6-membered heterocycloalkyl ring, pyrazolyl is an example of a5-membered heteroaryl ring, pyridyl is an example of a 6-memberedheteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a10-membered cycloalkyl group.

As used herein, the phrase “optionally substituted” means unsubstitutedor substituted. As used herein, the term “substituted” means that ahydrogen atom is removed and replaced by a substituent. It is to beunderstood that substitution at a given atom is limited by valency.

Throughout the definitions, the term “C_(n-m)” indicates a range whichincludes the endpoints, wherein n and m are integers and indicate thenumber of carbons. Examples include C₁₋₄, C₁₋₆, and the like.

As used herein, the term “C_(n-m) alkyl”, employed alone or incombination with other terms, refers to a saturated hydrocarbon groupthat may be straight-chain or branched, having n to m carbons. Examplesof alkyl moieties include, but are not limited to, chemical groups suchas methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, and the like. In some embodiments, thealkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms,from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

As used herein, “C_(n-m) alkenyl” refers to an alkyl group having one ormore double carbon-carbon bonds and having n to m carbons. Examplealkenyl groups include, but are not limited to, ethenyl, n-propenyl,isopropenyl, n-butenyl, sec-butenyl, and the like. In some embodiments,the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, “C_(n-m) alkynyl” refers to an alkyl group having one ormore triple carbon-carbon bonds and having n to m carbons. Examplealkynyl groups include, but are not limited to, ethynyl, propyn-1-yl,propyn-2-yl, and the like. In some embodiments, the alkynyl moietycontains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylene”, employed alone or incombination with other terms, refers to a divalent alkyl linking grouphaving n to m carbons. Examples of alkylene groups include, but are notlimited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl,butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl,2-methyl-propan-1,3-diyl, and the like. In some embodiments, thealkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to2 carbon atoms.

As used herein, the term “C_(n-m) alkoxy”, employed alone or incombination with other terms, refers to a group of formula —O-alkyl,wherein the alkyl group has n to m carbons. Example alkoxy groupsinclude methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy),tert-butoxy, and the like. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) aryloxy”, employed alone or incombination with other terms, refers to a group of formula —O-aryl,wherein the aryl group has n to m carbon atoms. Example aryloxy groupinclude, phenoxy and naphthyloxy.

As used herein, the term “C_(n-m) alkylamino” refers to a group offormula —NH(alkyl), wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkoxycarbonyl” refers to a group offormula —C(O)O-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “C_(n-m) alkylcarbonyl” refers to a group offormula —C(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylcarbonylamino” refers to a groupof formula —NHC(O)-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylsulfonylamino” refers to a groupof formula —NHS(O)₂-alkyl, wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “aminosulfonyl” refers to a group of formula—S(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonyl” refers to a groupof formula —S(O)₂NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonyl” refers to agroup of formula —S(O)₂N(alkyl)₂, wherein each alkyl group independentlyhas n to m carbon atoms. In some embodiments, each alkyl group has,independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminosulfonylamino” refers to a group offormula —NHS(O)₂NH₂.

As used herein, the term “C_(n-m) alkylaminosulfonylamino” refers to agroup of formula —NHS(O)₂NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminosulfonylamino” refers toa group of formula —NHS(O)₂N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “aminocarbonylamino”, employed alone or incombination with other terms, refers to a group of formula —NHC(O)NH₂.

As used herein, the term “C_(n-m) alkylaminocarbonylamino” refers to agroup of formula —NHC(O)NH(alkyl), wherein the alkyl group has n to mcarbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4,or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m) alkyl)aminocarbonylamino” refers toa group of formula —NHC(O)N(alkyl)₂, wherein each alkyl groupindependently has n to m carbon atoms. In some embodiments, each alkylgroup has, independently, 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamyl” refers to a group offormula —C(O)—NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “C_(n-m) alkylcarbamoyl” refers to a group offormula —OC(O)NH(alkyl), wherein the alkyl group has n to m carbonatoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to3 carbon atoms.

As used herein, the term “thio” refers to a group of formula —SH.

As used herein, the term “C_(n-m) alkylsulfinyl” refers to a group offormula —S(O)-alkyl, wherein the alkyl group has n to m carbon atoms. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) alkylsulfonyl” refers to a group offormula —S(O)₂-alkyl, wherein the alkyl group has n to m carbon atoms.In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3carbon atoms.

As used herein, the term “amino” refers to a group of formula —NH₂.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to an aromatic hydrocarbon group, which may bemonocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term“C_(n-m) aryl” refers to an aryl group having from n to m ring carbonatoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl,phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, arylgroups have from 6 to about 20 carbon atoms, from 6 to about 15 carbonatoms, or from 6 to about 10 carbon atoms. In some embodiments, the arylgroup is a substituted or unsubstituted phenyl.

As used herein, the term “carbamyl” to a group of formula —C(O)NH₂.

As used herein, the term “carbonyl”, employed alone or in combinationwith other terms, refers to a —C(═O)— group, which may also be writtenas C(O).

As used herein, the term “carbamoyl” refers to a group of formula—OC(O)NH₂.

As used herein, the term “cyano-C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-CN.

As used herein, the term “HO—C₁₋₃ alkyl” refers to a group of formula—(C₁₋₃ alkylene)-OH.

As used herein, the term “di(C_(n-m)-alkyl)amino” refers to a group offormula —N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamyl” refers to a groupof formula —C(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, the term “di(C_(n-m)-alkyl)carbamoyl” refers to a groupof formula —OC(O)N(alkyl)₂, wherein the two alkyl groups each has,independently, n to m carbon atoms. In some embodiments, each alkylgroup independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, ahalo is F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. Insome embodiments, a halo is Cl. In some embodiments, a halo is F.

As used herein, “C_(n-m) haloalkoxy” refers to a group of formula—O-haloalkyl having n to m carbon atoms. An example haloalkoxy group isOCF₃. In some embodiments, the haloalkoxy group is fluorinated only. Insome embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbonatoms.

As used herein, the term “C_(n-m) haloalkyl”, employed alone or incombination with other terms, refers to an alkyl group having from onehalogen atom to 2s+1 halogen atoms which may be the same or different,where “s” is the number of carbon atoms in the alkyl group, wherein thealkyl group has n to m carbon atoms. In some embodiments, the haloalkylgroup is fluorinated only. In some embodiments, the alkyl group has 1 to6, 1 to 4, or 1 to 3 carbon atoms.

As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbonsincluding cyclized alkyl and/or alkenyl groups. Cycloalkyl groups caninclude mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groupsand spirocycles. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10ring-forming carbons (C₃₋₁₀). Ring-forming carbon atoms of a cycloalkylgroup can be optionally substituted by oxo or sulfido (e.g., C(O) orC(S)). Cycloalkyl groups also include cycloalkylidenes. Examplecycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl,cycloheptatrienyl, norbornyl, norpinyl, norcaranyl, and the like. Insome embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cyclopentyl, or adamantyl. In some embodiments, thecycloalkyl has 6-10 ring-forming carbon atoms. In some embodiments,cycloalkyl is adamantyl. Also included in the definition of cycloalkylare moieties that have one or more aromatic rings fused (i.e., having abond in common with) to the cycloalkyl ring, for example, benzo orthienyl derivatives of cyclopentane, cyclohexane, and the like. Acycloalkyl group containing a fused aromatic ring can be attachedthrough any ring-forming atom including a ring-forming atom of the fusedaromatic ring.

As used herein, “heteroaryl” refers to a monocyclic or polycyclicaromatic heterocycle having at least one heteroatom ring member selectedfrom sulfur, oxygen, and nitrogen. In some embodiments, the heteroarylring has 1, 2, 3, or 4 heteroatom ring members independently selectedfrom nitrogen, sulfur and oxygen. In some embodiments, any ring-formingN in a heteroaryl moiety can be an N-oxide. In some embodiments, theheteroaryl has 5-10 ring atoms and 1, 2, 3 or 4 heteroatom ring membersindependently selected from nitrogen, sulfur and oxygen. In someembodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatomring members independently selected from nitrogen, sulfur and oxygen. Insome embodiments, the heteroaryl is a five-membered or six-memberedheteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with aring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ringatoms are independently selected from N, O, and S. Exemplaryfive-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl,thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl,1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl,1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl,1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroarylring is a heteroaryl with a ring having six ring atoms wherein one ormore (e.g., 1, 2, or 3) ring atoms are independently selected from N, O,and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl,pyrimidinyl, triazinyl and pyridazinyl.

As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic orpolycyclic heterocycles having one or more ring-forming heteroatomsselected from O, N, or S. Included in heterocycloalkyl are monocyclic4-, 5-, 6-, and 7-membered heterocycloalkyl groups. Heterocycloalkylgroups can also include spirocycles. Example heterocycloalkyl groupsinclude pyrrolidin-2-on-yl, 1,3-isoxazolidin-2-on-yl, pyranyl,tetrahydropyranyl, oxetanyl, azetidinyl, morpholinyl, thiomorpholinyl,piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, andthe like. Ring-forming carbon atoms and heteroatoms of aheterocycloalkyl group can be optionally substituted by oxo or sulfido(e.g., C(O), S(O), C(S), or S(O)₂, etc.). The heterocycloalkyl group canbe attached through a ring-forming carbon atom or a ring-formingheteroatom. In some embodiments, the heterocycloalkyl group contains 0to 3 double bonds. In some embodiments, the heterocycloalkyl groupcontains 0 to 2 double bonds. Also included in the definition ofheterocycloalkyl are moieties that have one or more aromatic rings fused(i.e., having a bond in common with) to the cycloalkyl ring, forexample, benzo or thienyl derivatives of piperidine, morpholine,azepine, etc. A heterocycloalkyl group containing a fused aromatic ringcan be attached through any ring-forming atom including a ring-formingatom of the fused aromatic ring. In some embodiments, theheterocycloalkyl has 4-10, 4-7 or 4-6 ring atoms with 1 or 2 heteroatomsindependently selected from nitrogen, oxygen, or sulfur and having oneor more oxidized ring members.

At certain places, the definitions or embodiments refer to specificrings (e.g., a furan ring, a pyridine ring, etc.). Unless otherwiseindicated, these rings can be attached to any ring member provided thatthe valency of the atom is not exceeded. For example, an azetidine ringmay be attached at any position of the ring, whereas a pyridin-3-yl ringis attached at the 3-position.

The term “compound” as used herein is meant to include allstereoisomers, geometric isomers, tautomers, and isotopes of thestructures depicted. Compounds herein identified by name or structure asone particular tautomeric form are intended to include other tautomericforms unless otherwise specified.

Compounds provided herein also include tautomeric forms. Tautomericforms result from the swapping of a single bond with an adjacent doublebond together with the concomitant migration of a proton. Tautomericforms include prototropic tautomers which are isomeric protonationstates having the same empirical formula and total charge. Exampleprototropic tautomers include ketone-enol pairs, amide-imidic acidpairs, lactam-lactim pairs, enamine-imine pairs, and annular forms wherea proton can occupy two or more positions of a heterocyclic system, forexample, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution.

All compounds, and pharmaceutically acceptable salts thereof, can befound together with other substances such as water and solvents (e.g.hydrates and solvates) or can be isolated.

In some embodiments, preparation of compounds can involve the additionof acids or bases to affect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids and include, but are notlimited to, strong and weak acids. Some example acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid,benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some weakacids include, but are not limited to acetic acid, propionic acid,butanoic acid, benzoic acid, tartaric acid, pyroglutamic acid, gulonicacid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid,nonanoic acid, and decanoic acid. Also included are organic diacids suchas malonic, fumaric and maleic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, potassium carbonate, andsodium bicarbonate. Some example strong bases include, but are notlimited to, hydroxide, alkoxides, metal amides, metal hydrides, metaldialkylamides and arylamines, wherein; alkoxides include lithium, sodiumand potassium salts of methyl, ethyl and t-butyl oxides; metal amidesinclude sodium amide, potassium amide and lithium amide; metal hydridesinclude sodium hydride, potassium hydride and lithium hydride; and metaldialkylamides include lithium, sodium, and potassium salts of methyl,ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, trimethylsilyl andcyclohexyl substituted amides.

In some embodiments, the compounds provided herein, or salts thereof,are substantially isolated. By “substantially isolated” is meant thatthe compound is at least partially or substantially separated from theenvironment in which it was formed or detected. Partial separation caninclude, for example, a composition enriched in the compounds providedherein. Substantial separation can include compositions containing atleast about 50%, at least about 60%, at least about 70%, at least about80%, at least about 90%, at least about 95%, at least about 97%, or atleast about 99% by weight of the compounds provided herein, or saltthereof. Methods for isolating compounds and their salts are routine inthe art.

The expressions, “ambient temperature” and “room temperature” or “rt” asused herein, are understood in the art, and refer generally to atemperature, e.g. a reaction temperature, that is about the temperatureof the room in which the reaction is carried out, for example, atemperature from about 20° C. to about 30° C.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present application also includes pharmaceutically acceptable saltsof the compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present application include the conventionalnon-toxic salts of the parent compound formed, for example, fromnon-toxic inorganic or organic acids. The pharmaceutically acceptablesalts of the present application can be synthesized from the parentcompound which contains a basic or acidic moiety by conventionalchemical methods. Generally, such salts can be prepared by reacting thefree acid or base forms of these compounds with a stoichiometric amountof the appropriate base or acid in water or in an organic solvent, or ina mixture of the two; generally, non-aqueous media like ether, ethylacetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) oracetonitrile (MeCN) are preferred. Lists of suitable salts are found inRemington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company,Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2(1977). Conventional methods for preparing salt forms are described, forexample, in Handbook of Pharmaceutical Salts: Properties, Selection, andUse, Wiley-VCH, 2002.

Methods of Use

Provided herein are methods of treating a disease in a subject in needthereof. As used herein, the term “subject,” refers to any animal,including mammals. For example, mice, rats, other rodents, rabbits,dogs, cats, swine, cattle, sheep, horses, primates, and humans. In someembodiments, the subject is a human. In some embodiments, the methodcomprises administering to the subject a therapeutically effectiveamount of a compound provided herein (e.g., a compound of Formula (I)),or a pharmaceutically acceptable salt thereof. In some embodiments, thedisease is a disease associated with one or more mRNA splicing defects.

The present application further provides a method of treating a diseaseassociated with one or more mRNA splicing defects in a subject in needthereof, comprising administering to the subject a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula (I)). In some embodiments, the disease associated with the oneor more mRNA splicing defects is a disease of the central nervoussystem.

In some embodiments of the methods provided herein, the compound isselected from the group of compounds provided in Table A, or apharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from the group of compounds provided in Table A-2,or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from the group of compounds provided in Table A-3,or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from the group of compounds provided in Table B, ora pharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from the group of compounds provided in Table B-2,or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from the group of compounds provided in Table B-3,or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound is selected from the group of compounds provided in Table C, ora pharmaceutically acceptable salt thereof.

Example diseases of the central nervous system include, but are notlimited to, Alzheimer's disease, amyotrophic lateral sclerosis (ALS),attention deficit/hyperactivity disorder (ADHD), atypical cysticfibrosis, autism, autism spectrum disorders, Bell's Palsy, bipolardisorder, catalepsy, Cerebral Palsy, Charcot-Marie-Tooth disease, Chargesyndrome, depression, dementia, epilepsy, epileptic encephalopathy,encephalitis, familial dysautomonia (FD), familial isolated growthhormone deficiency type II (IGHD II), Frasier syndrome, frontotemporaldementia and Parkinson's linked to Chromosome 17 (FTDP-17), Huntington'sdisease, locked-in syndrome, major depressive disorder, Marfan syndrome,meningitis, mental retardation, Menkes Disease (MD), migraine, multiplesclerosis (MS), muscular dystrophies (e.g., Duchenne Muscular Dystrophy,Becker Muscular Dystrophy, Ullrich congenital muscular dystrophy,Asphyxiating thoracic dystrophy, Fukuyama Muscular dystrophy, Spinalmuscular atrophy with respiratory distress 1, Congenital Musculardystrophy 1A, Muscular dystrophy with epidermolysis bullosa,Facioscapulohumeral-like muscular dystrophy), myopathies (e.g., Bethlemmyopathy, Collagen VI myopathy, Myotubular myopathy, Nemaline myopathy,Proximal myopathy and learning difficulties, Desmin related Myopathy andCongenital Myopathy with cores), neurofibromatosis 1 (NF1, vonRecklinghausen NF; peripheral NF), neurofibromatosis 2 (NF2), occipitalhorn syndrome, Parkinson's disease, retinoblastoma, Rett syndrome,schizophrenia, tropical spastic paraparesis, Tourette's syndrome, andtuberous sclerosis. In some embodiments, the disease associated with oneor more mRNA splicing defects is a disease listed in Table 1.

In some embodiments, the disease associated with one or more mRNAsplicing defects is selected from the group consisting of amyotrophiclateral sclerosis (ALS), atypical cystic fibrosis, autism, autismspectrum disorders, Charcot-Marie-Tooth disease, Charge syndrome,dementia, epilepsy, epileptic encephalopathy, familial dysautonomia(FD), familial isolated growth hormone deficiency type II (IGHD II),Frasier syndrome, frontotemporal dementia and Parkinson's linked toChromosome 17 (FTDP-17), Huntington's disease, Marfan syndrome, mentalretardation, Menkes Disease (MD), muscular dystrophies (e.g., DuchenneMuscular Dystrophy, Becker Muscular Dystrophy, Ullrich congenitalmuscular dystrophy, Asphyxiating thoracic dystrophy, Fukuyama Musculardystrophy, Spinal muscular atrophy with respiratory distress 1,Congenital Muscular dystrophy 1A, Muscular dystrophy with epidermolysisbullosa, Facioscapulohumeral-like muscular dystrophy), myopathies (e.g.,Bethlem myopathy, Collagen VI myopathy, Myotubular myopathy, Nemalinemyopathy, Proximal myopathy and learning difficulties, Desmin relatedMyopathy and Congenital Myopathy with cores), myotonic dystrophy type 1(DM1), myotonic dystrophy type 2 (DM2), neurofibromatosis 1 (NF1, vonRecklinghausen NF; peripheral NF), occipital horn syndrome, Parkinson'sdisease, retinoblastoma, schizophrenia, and tuberous sclerosis.

In some embodiments, the disease associated with one or more mRNAsplicing defects is a disease listed in Table 1; for example, bilateraltemporooccipital polymicrogyria; amyotrophic lateral sclerosis;Charcot-Marie-Tooth disease; Yunis-Varon syndrome; juvenile onsetParkinson disease 19; juvenile-onset neurodegeneration with brain ironaccumulation; Parkinson disease 8; autosomal recessive spasticparaplegia 43; periventricular heterotopia with microcephaly; X linkedmental retardation 46; Coach syndrome; Joubert syndrome 9; Meckelsyndrome 6; X linked mental retardation syndromic 15, Cabezas type; Xlinked mental retardation syndromic, Claes-Jensen type; autosomaldominant mental retardation 1; X linked mental retardation, withcerebellar hypoplasia and distinctive facial appearance; autosomalrecessive mental retardation 42; arthrogryposis; hypokalemic periodicparalysis, type 1; malignant hyperthermia susceptibility 5;susceptibility to thyrotoxic periodic paralysis 1; Angelmansyndrome-like; early infantile epileptic encephalopathy; Fragile Xsyndrome; Fragile X-tremor/ataxia syndrome; premature ovarian failure 1;Cornelia de Lange syndrome 5; Wilson-Turner syndrome; Angelman syndrome;neonatal severe encephalopathy; X-linked syndromic, Lubs type mentalretardation; X-linked syndromic mental retardation 13; Rett syndrome;preserved speech variant Rett syndrome; X-linked autism susceptibility3; cerebral creatine deficiency syndrome 1; autosomal dominant mentalretardation 5; childhood onset epileptic encephalopathy; epilepsy;Dravet syndrome; primary erythermalgia; familial febrile seizures 3B;autosomal recessive HSAN2D; paroxysmal extreme pain disorder/small fiberneuropathy; Dravet syndrome modifier of epileptic encephalopathy; earlyinfantile 4 and 18; dilated cardiomyopathy 3B; Bethlem myopathy;short-rib thoracic dysplasia 3 with or without polydactylycardiomyopathy, dilated, 1×; neuronopathy type VI; epidermolysis bullosasimplex with pyloric atresia; epidermolysis bullosa simplex, Ogna type;King-Denborough syndrome; minicore myopathy with externalophthalmoplegia; congnenital neuromuscular disease with uniform type 1fiber; malignant hyperthermia susceptibility 1; Taylor balloon cell typefocal cortical dysplasia; lymphangioleiomyomatosis; tuberoussclerosis-1; somatic lymphangioleiomyomatosis; tuberous sclerosis-2;acromicric dysplasia; ascending and dissection aortic aneurysm; familialectopia lentis; Mass syndrome; stiff skin syndrome; dominantWeill-Marchesani syndrome 2; somatic bladder cancer; somaticosteosarcoma; retinoblastoma; small cell lung cancer; somatic Chargesyndrome; hypogonadotropic hypogonadism 5 with or without anosmia; and,idiopathic scoliosis 3.

In some embodiments, the disease associated with one or more mRNAsplicing defects is selected from familial dysautonomia andneurofibromatosis 1. In some embodiments, the disease associated withone or more mRNA splicing defects is familial dysautonomia. In someembodiments, the disease associated with one or more mRNA splicingdefects is neurofibromatosis 1.

In some embodiments, the one or more mRNA splicing defects is associatedwith one or more genes comprising at least one exon comprising thenucleotide sequence CAA. In some embodiments, the one or more genescomprising at least one exon comprising the nucleotide sequence CAA isassociated with a disease of the central nervous system. In someembodiments, the one or more genes comprising at least one exoncomprising the nucleotide sequence CAA is selected from the groupprovided in Table 1, wherein all references cited herein areincorporated by reference herein in their entirety.

TABLE 1 GeneBank Acc. Human Gene No. for Human Name Gene AssociatedDiseases References Inhibitor of kappa NG_008788.1 Dysautonomia,Anderson et al., Am. J. Hum. light polypeptide familial Genet. 68:753-758, 2001; gene enhancer in B Slaugenhaup et al. Am. J., Hum. cells,kinase Genet. 68: 598-605, 2001 complex-associated protein (IKBKAP SACdomain- NG_007977.1 Polymicrogyria, Chow et al Nature 448: 68-72,containing inositol bilateral 2007; Chow et al., Am. J. Hum. phosphatase3 temporooccipital, Genet. 84: 85-88, 2009; Campeau (FIG4) Amyotrophiclateral et al., Am. J. Hum. Genet. 92: 781- sclerosis 11, 791, 2013;Charcot-Marie- Baulac et al., Neurology 82: 1068- Tooth disease, type1075, 2014 4J, Yunis-Varon syndrome DNAJ/HSP40 NG_033843.1 Parkinsondisease Edvardson et al., PLoS One 7: homology subfamily 19,juvenile-onset e36458, 2012; Koroglu et al., C member 6 ParkinsonismRelat. Disord. 19: (DNAJC6) 320-324, 2013 WD40 repeat- NG_033004.1Neurodegeneration Haack et al., Am. J. Hum. Genet. containing proteinwith brain iron 91: 1144-1149, 2012; Saitsu et al., 45 (WDR45)accumulation 5 Nature Genet. 45: 445-449, 2013. Leucine-rich repeatNG_011709.1 Parkinson disease 8 Zimprich et al., Neuron 44: 601- kinase2 (LRRK2) 607, 2004; Tan et al., Hum. Mutat. 31: 561-568, 2010Leucine-rich repeat- NG_032008.1 Charcot-Marie- Guernsey et al., PLOSGenet. 6: and sterile alpha Toothe disease, e1001081, 2010; Nicolaou etal., motif-containing 1 axonal, type 2P Europ. J. Hum. Genet. 21: 190-(LRSAM1) 194, 2013 SET-binding factor NG_008074.1 Charcot-Marie-Senderek et al., Hum. Molec. 2 (SBF2) Tooth disease, type Genet. 12:349-356, 2003; 4B2 Azzedine et al., Am. J. Hum. Genet. 72: 1141-1153,2003 Chromosome 10 NG_031970.1 Spastic paraplegia Hogarth et al.,Neurology 80: 268- open reading frame 43, autosomal 275, 2013; Meilleuret al., 12 (C19orf12) recessive; Neurogenetics 11: 313-318, 2010Neurodegeneration with brain iron accumulation 4 ADP-ribosylationNG_011490.1 Periventricular Banne et al., J. Med. Genet. 50: factorguanine heterotopia with 772-775, 2013 nucleotide-exchange microcephalyfactor 2 (brefeldin A-inhibited) (ARFGEF2) RHO guanine NG_008873.1Mental retardation, Yntema et al., J. Med. Genet. 35: nucleotideexchange X-linked 46 801-805, 1998; Kutsche et al., factor 6(ARHGEF6)Nature Genet. 26: 247-250, 2000 Coiled-coil and C2 NG_013035.1 COACHsyndrome; Noor et al., DNA Res. 7: 65-73, domain-containing Joubertsyndrome 9; 2000; Tallila et al., Am. J. Hum. protein 2A Meckel syndrome6 Genet. 82: 1361-1367, 2008; (CC2D2A) Doherty et al., J. Med. Genet.47: 8-21, 2010 Chromodomain NG_021249.1 Autism, O'Roak et al., Science338: 1619- helicase DNA- susceptibility 1622, 2012 binding protein 8(CHD8) Cullin 4b (CUL4B) NG_009388.1 Mental retardation, Tarpey et al.,Nature Genet. 41: X-linked, syndromic 535-543, 2009 15 (Cabezas type)Lysine-specific NG_008085.1 Mental retardation, Jensen et al., Am. J.Hum. Genet. demethylase 5C X-linked, 76: 227-236, 2005 (KDM5C)syndromic, Claes- Jensen type Methyl-CpG- NG_017003.1 Mentalretardation, Wagenstaller et al., Am. J. Hum. binding domain autosomaldominant Genet. 81: 768-779, 2007 protein 5 (MBD5) 1 Oligophrenin1NG_008960.1 Mental retardation, Zanni et al., Neurology 65: 1364-(OPHN1) X-linked, with 1369, 2005 cerebellar hypoplasia and distinctivefacial appearance Post-GPI attachment NC_000002.12 Mental retardation,Murakami et al., PLoS Genet. 10: to proteins 1 Range: autosomalrecessive e1004320, 2014 (PGAP1) 196833004 . . . 196926995 42 Solutecarrier family NG_017077.1 Autism Morrow et al., Science 321: 218- 9(sodium/hydrogen susceptibility 223, 2008 exchanger) member 9 (SLC9A9)Solute carrier family NG_033857.1 Arthrogryposis, Edvardson et al., J.Med. Genet. 35 (UDP-N- mental retardation, 50: 733-739, 2013.acetylglucosamine and seizures transporter) member 3 (SLC35A3) Calciumchannel, NG_009816.1 Hypokalemic Ptacek et al., Cell 77: 863-868,voltage-dependent, periodic paralysis, 1994; Monnier et al., Am. J. Hum.L Type, alpha-1S type 1; Malignant Genet. 60: 1316-1325, 1997; Kungsubunit hyperthermia et al., J. Clin. Endocr. Metab. 89: (CACNA1S)susceptibility 5; 1340-1345, 2004 Thyrotoxic periodic paralysis,susceptibility to, 1 Cyclin-dependent NG_008475.1 Angelman Van Esch etal., Am. J. Med. kinase-like 5 syndrome-like; Genet. 143A: 364-369,2007; (CDKL5) Epileptic Nemos et al., Clin. Genet. 76: 357-encephalopathy, 371, 2009. early infantile, 2 Fragile X mentalNG_007529.1 Fragile X syndrome; Devys et al., Nature Genet. 4: 335-retardation protein Fragile X 340, 1993; Allingham-Hawkins et (FMR1)tremor/ataxia al., Am. J. Med. Genet. 83: 322- syndrome; 325, 1999;Leehey et al., Arch. Premature ovarian Neurol. 60: 117-121, 2003 failure1 Histone deacetylase NG_015851.1 Cornelia de Lange Harakalova et al.,J. Med. Genet. 8 (HDAC8) syndrome 5; Wilson- 49: 539-543, 2012;Deardorff et Turner syndrome al., Nature 489: 313-317, 2012 Methyl-CpG-NG_007107.2 Angelman Wan et al., Hum. Molec. Genet. binding protein 2syndrome; 10: 1085-1092, 2001; Xiang et al., (MECP2) Encephalopathy, J.Med. Genet. 37: 250-255, 2000; neonatal severe; Meloni et al., Am. J.Hum. Genet. Mental retardation, 67: 982-985, 2000; Watson et al.,X-linked syndromic, J. Med. Genet. 38: 224-228, 2001; Lubs type; MentalCarney et al., Pediat. Neurol. 28: retardation, X- 205-211, 2003 linked,syndromic 13; Rett syndrome; Rett syndrome, preserved speech variant;Autism susceptibility, X- linked 3 Solute carrier family NG_012016.1Cerebral creatine Salomons et al., Am. J. Hum. 6 (neurotransmitterdeficiency syndrome Genet. 68: 1497-1500, 2001 transporter creatine) 1member 8(SLC6A8) Synaptic RAS- NG_016137.1 Mental retardation, Hamdan etal., Biol. Psychiat. 69: GTPase-activating autosomal dominant 898-901,2011 protein 1 5 (SYNGAP1) Chromodomain NG_012826.1 Epileptic Carvill etal., Nature Genet. 45: helicase DNA- encephalopathy, 825-830, 2013binding protein 2 childhood-onset (CHD2) Cholinergic NG_011931.1Epilepsy, nocturnal Steinlein et al., Nature Genet. 11: receptor,neuronal frontal lobe, 1; 201-203, 1995; Li et al., Hum. nicotinic,alpha Nicotine addiction, Molec. Genet. 14: 1211-1219, polypeptide 4susceptibility to 2005 (CHRNA4) DEP domain- NG_034067.1 Epilepsy,familial Dibbens et al., Nature Genet. 45: containing protein 5 focal,with variable 546-551, 2013 (DEPDC5) foci Golgi SNAP NG_031806.1Epilepsy, Corbett et al., Am. J. Hum. Genet. receptor complexprogressive 88: 657-663, 2011 member 2 (GOSR2) myoclonic 6 Glutamatereceptor, NG_011812.1 Epilepsy, focal, with Carvill et al., NatureGenet. 45: ionotropic, N- speech disorder and 1073-1076, 2013methyl-D-aspartate, with or without subunit 2A mental retardation(GRIN2A) Sodium channel, NG_011906.1 Dravet syndrome; Baulac et al., Am.J. Hum. Genet. neuronal type 1, Epilepsy, 65: 1078-1085, 1999; Claes etal., alpha subunit generalized, with Am. J. Hum. Genet. 68: 1327-(SCN1A) febrile seizures plus, 1332, 2001; Ohmori et al., type 2;Febrile Biochem. Biophys. Res. Commun. seizures, familial, 295: 17-23,2002 3A; Migraine, familial hemiplegic, 3 Sodium channel, NG_012798.1Epilepsy, Yang et al., J. Med. Genet. 41: voltage-gated, typegeneralized, with 171-174, 2004; Faber et al., Ann. 1X, alpha subunitfebrile seizures plus, Neurol. 71: 26-39, 2012; Goldberg (SCN9A) type 7;et al., Clin. Genet. 71: 311-319, Erythermalgia, 2007; Catterall et al.,Neuron 52: primary; Febrile 743-749, 2006; Singh et al., PLoS seizures,familial, Genet. 5: e1000649, 2009 3B; HSAN2D, autosomal recessive;Paroxysmal extreme pain disorder, Small fiber neuropathy; Dravetsyndrome, modifier of Syntaxin-binding NG_016623.1 Epileptic Saitsu etal., Nature Genet. 40: protein 1 (STXBP1) encephalopathy, 782-788, 2008early infantile, 4 Seizure threshold 2 NG_029091.1 EpilepticBasel-Vanagaite et al., Am. J. (SZT2) encephalopathy, Hum. Genet. 93:524-529, 2013 early infantile, 18 Dystrophin (DMD) NG_012232.1 Beckermuscular Gurvich et al., Hum. Mutat. 30: dystrophy; 633-640, 2009;Muntoni et al., Cardiomyopathy, Am. J. Hum. Genet. 56: 151-157, dilated,3B; 1995; Daoud et al., Hum. Molec. Duchenne muscular Genet. 18:3779-3794, 2009 dystrophy Collagen type VI, NG_008676.1 Bethlemmyopathy; Demir et al., Am. J. Hum. Genet. alpha-3 (COL6A3) Ullrichcongenital 70: 1446-1458, 2002; Lampe et al., muscular dystrophy J. Med.Genet. 42: 108-120, 2005 Dynein, cytoplasmic NG_016423.1 Short-ribthoracic Dagoneau et al., Am. J. Hum. 2 heavy chain 1 dysplasia 3 withor Genet. 84: 706-711, 2009 (DYNC2H1) without polydactyly Fukutin (FKTN)NG_008754.1 Cardiomyopathy, Taniguchi-Ikeda et al., 478: 127- dilated,1X; 131, 2011 Muscular dystrophy- dystroglycanopathy (congenital withbrain and eye anomalies), type A4, B4 and C4 Immunoglobin 2 NG_007976.1Charcot-Marie- Grohmann et al., Nature Genet. 29: MU-binding Toothdisease, 75-77, 2001; Cottenie et al., Am. J. protein2 axonal, type 2S;Hum. Genet. 95: 590-601, 2014 (IGHMBP2) Neuronopathy, distal hereditarymotor, type VI Laminin alpha-2 NG_008678.1 Muscular dystrophy, Tezak etal., Hum. Mutat. 21: 103- (LAMA2) congenital merosin- 111, 2003;Oliveira et al., Clin. deficient; Muscular Genet. 74: 502-512, 2008dystrophy, congenital, due to partial LAMA2 deficiency Myotubularin 1NG_008199.1 Myotubular Tanner et al., Hum. Mutat. 11: 62- (MTM1)myopathy, X-linked 68, 1998 Nebulin (NEB) NG_009382.2 Nemaline myopathyDonner et al., Europ. J. Hum. 2, autosomal Genet. 12: 744-751, 2004;recessive Lehtokari et al., Hum. Mutat. 27: 946-956, 2006 Plectin (PLEC)NG_012492.1 Epidermolysis Pulkkinen et al., Hum. Molec. bullosa simplexwith Genet. 5: 1539-1546, 1996; pyloric atresia; Pfendner et al., J.Invest. Derm. Epidermolysis 124: 111-115, 2005 bullosa simplex, Ognatype; Muscular dystrophy with epidermolysis bullosa simplex; Musculardystrophy, limb-girdle, type 2Q Mitochondrial NG_033179.1 Myopathy withLogan et al., Nature Genet. 46: calcium uptake extrapyramidal signs188-193, 2014 protein 1 (MICU1) Structural NG_031972.1Fascioscapulohumeral Lemmers et al., Nature Genet. 44: maintenance ofmuscular 1370-1374, 2012 chromosomes dystrophy 2, digenic flexible hingedomain-containing protein 1 (SMCHD1) Desmin (DES) NG_008043.1 Musculardystrophy, Dalakas et al., New Eng. J. Med. limb-girdle, type 2R; 342:770-780, 2000; Li et al., Cardiomyopathy, Circulation 100: 461-464,1999; dilated, 1I; Walter et al., Brain 130: 1485- Myopathy, 1496, 2007;Cetin et al., J. Med. myofibrillar, 1; Genet. 50: 437-443, 2013Scapuloperoneal syndrome, neurogenic, Kaeser type Ryanodine receptorNG_008866.1 Central core disease; Sambuughin et al., Am. J. Hum. 1(RYR1) King-Denborough Genet. 69: 204-208, 2001; Tilgen syndrome;Minicore et al., Hum. Molec. Genet. 10: myopathy with 2879-2887, 2001;Monnier et al., external Hum. Molec. Genet. 12: 1171- ophthalmoplegia;1178, 2003; D'Arcy et al., Neuromuscular Neurology 71: 776-777, 2008disease, congenital, with uniform type 1 fiber; Malignant hyperthermiasusceptibility 1 Hamartin(TSC1) NG_012386.1 Focal cortical Iyer et al.,Science 338: 222, 2012; dysplasia, Taylor Becker et al., Ann. Neurol.52: 29- balloon cell type; 37, 2002; Jones et al., Hum. Lymphangioleio-Molec. Genet. 6: 2155-2161, 1997 myomatosis; Tuberous sclerosis-1Tuberin (TSC2) NG_005895.1 Lymphangioleio- Carbonara et al., Genesmyomatosis, somatic; Chromosomes Cancer 15: 18-25, Tuberous sclerosis-21996; Carsillo et al., Proc. Nat. Acad. Sci. 97: 6085-6090, 2000Fibrillin 1 (FBN1) NG_008805.2 Acromicric Dietz et al., Nature 352:337-339, dysplasia; Aortic 1991; Faivre et al., J. Med. Genet. aneurysm,40: 34-36, 2003; Loeys et al., Sci. ascending, and Transl. Med. 2:23ra20, 2010; Le dissection; Ectopia Goff et al., Am. J. Hum. Genet. 89:lentis, familial; 7-14, 2011 Marfan syndrome; MASS syndrome; Stiff skinsyndrome; Weill-Marchesani syndrome 2, dominant Retinoblastoma 1NG_009009.1 Bladder cancer, Yandell et al., New Eng. J. Med. (RB1)somatic; 321: 1689-1695, 1989; Harbour et Osteosarcoma, al., Science241: 353-357, 1988 somatic; Retinoblastoma; Retinoblastoma, trilateral;Small cell cancer of the lung, somatic Chromodomain NG_007009.1 CHARGELalani et al., Am. J. Hum. Genet. helicase DNA- syndrome; 78: 303-314,2006; Kim et al., Am. binding protein 7 Hypogonadotropic J. Hum. Genet.83: 511-519, 2008; (CHD7) hypogonadism 5 Gao et al., Am. J. Hum. Genet.80: with or without 957-965, 2007; Felix et al., Am. J. anosmia;Scoliosis, Med. Genet. 140A: 2110-2114, idiopathic 3 2006; Pleasance etal., Nature 463: 184-190, 2010

In some embodiments, the one or more mRNA splicing defects is associatedwith one or more genes selected from the group consisting of BMP2K,ABI2, IKBKAP, FIG4, DNAJC6, WDR45, LRRK2, LRSAM1, SBF2, C19orf12,ARFGEF2, ARHGEF6, CC2D2A, CHD8, CUL4B, KDM5C, MBD5, OPHN1, PGAP1,SLC9A9, SLC35A3, CACNA1S, CDKL5, FMR1, HDAC8, MECP2, SLC6A8, SYNGAP1,CHD2, CHRNA4, DEPDC5, GOSR2, GRIN2A, SCN1A, SCN9A, STXBP1, SZT2, DMD,COL6A3, DYNC2H1, FKTN, IGHMBP2, LAMA2, MTM1, NEB, PLEC, MICU1, SMCHD1,DES, RYR1, TSC1, TSC2, FBN1, RB1, and CHD7. In some embodiments, the oneor more mRNA splicing defects is associated with one or more genesselected from the group provided in Table 1; in some embodiments, themRNA splicing defect causes or contributes to a disease listed in Table1.

The present application further provides a method of improving mRNAsplicing of a gene, e.g., in a cell or a subject, e.g., in a cell or asubject who has an mRNA splicing defect, e.g., a genetic mutationassociated with an mRNA splicing defect or a disease associated with anmRNA splicing defect. In some embodiments, the gene comprises at leastone exon comprising the nucleotide sequence CAA. In some embodiments,the method of improving mRNA splicing of a gene comprises contacting thegene (e.g., in a cell or subject expressing the gene) with a compoundprovided herein (e.g., a compound of Formula (I)). In some embodiments,the method of improving mRNA splicing of a gene comprises contacting agene (e.g., a cell expressing a gene) selected from the group consistingof BMP2K, ABI2, IKBKAP, FIG4, DNAJC6, WDR45, LRRK2, LRSAM1, SBF2,C19orf12, ARFGEF2, ARHGEF6, CC2D2A, CHD8, CUL4B, KDM5C, MBD5, OPHN1,PGAP1, SLC9A9, SLC35A3, CACNA1S, CDKL5, FMR1, HDAC8, MECP2, SLC6A8,SYNGAP1, CHD2, CHRNA4, DEPDC5, GOSR2, GRIN2A, SCN1A, SCN9A, STXBP1,SZT2, DMD, COL6A3, DYNC2H1, FKTN, IGHMBP2, LAMA2, MTM1, NEB, PLEC,MICU1, SMCHD1, DES, RYR1, TSC1, TSC2, FBN1, RB1, and CHD7 with acompound provided herein (e.g., a compound of Formula (I)); in someembodiments, the cell has an mRNA splicing defect in processingtranscripts from the gene, e.g., the cell has a mutation that causes amRNA splicing defect in processing transcripts from the gene. In someembodiments, the method of improving mRNA splicing of a gene comprisesimproving exon inclusion (e.g., wherein the mRNA splicing defect resultsin aberrant exon exclusion when compared to a wild-type cell or mRNA).

In some embodiments, the method of improving mRNA splicing of a genecomprises improving exon inclusion, wherein the gene is selected fromthe group consisting of BMP2K, ABI2, IKBKAP, FIG4, DNAJC6, WDR45, LRRK2,LRSAM1, SBF2, C19orf12, ARFGEF2, ARHGEF6, CC2D2A, CHD8, CUL4B, KDM5C,MBD5, OPHN1, PGAP1, SLC9A9, SLC35A3, CACNA1S, CDKL5, FMR1, HDAC8, MECP2,SLC6A8, SYNGAP1, CHD2, CHRNA4, DEPDC5, GOSR2, GRIN2A, SCN1A, SCN9A,STXBP1, SZT2, DMD, COL6A3, DYNC2H1, FKTN, IGHMBP2, LAMA2, MTM1, NEB,PLEC, MICU1, SMCHD1, DES, RYR1, TSC1, TSC2, FBN1, RB1, and CHD. In someembodiments, the method of improving mRNA splicing of a gene comprisesimproving exon inclusion, wherein the gene is selected from the groupprovided in Table 1.

In some embodiments, contacting the gene is performed in vitro. In someembodiments, contacting the gene is performed in vivo, e.g., in asubject who has a disease described herein and/or listed in Table 1.

In some embodiments, the compound (i.e., a compound of Formula (I)) foruse in the methods described herein may be used in combination with oneor more of the compounds provided and described in the presentdisclosure.

As used herein, the expression “EC_(k)” refers to the compoundconcentration at which the maximum kinetin efficacy (200 μM) is reached.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician. In some embodiments, the dosage ofthe compound, or a pharmaceutically acceptable salt thereof,administered to a subject or individual is about 1 mg to about 2 g,about 1 mg to about 1000 mg, about 1 mg to about 500 mg, about 1 mg toabout 100 mg, about 1 mg to 50 mg, or about 50 mg to about 500 mg.

As used herein, the term “treating” or “treatment” refers to one or moreof (1) preventing the disease; for example, preventing a disease,condition or disorder in an individual who may be predisposed to thedisease, condition or disorder but does not yet experience or displaythe pathology or symptomatology of the disease; (2) inhibiting thedisease; for example, inhibiting a disease, condition or disorder in anindividual who is experiencing or displaying the pathology orsymptomatology of the disease, condition or disorder (i.e., arrestingfurther development of the pathology and/or symptomatology); and (3)ameliorating the disease; for example, ameliorating a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,reversing the pathology and/or symptomatology) such as decreasing theseverity of disease or reducing or alleviating one or more symptoms ofthe disease.

Also provided herein are methods for increasing IKAP protein expressionin a patient in need thereof, the method comprising administering aneffective amount of a compound provide herein, (i.e., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof), to thepatient. For example, such methods include increasing IKAP proteinexpression in serum samples from the patient. Further provided hereinare methods for increasing the mean percentage of IKAP proteinexpression in a patient in need thereof, the method comprisingadministering an effective amount of a compound provided herein (i.e., acompound of Formula (I), or a pharmaceutically acceptable salt thereof,to the patient.

Also provided herein are methods for increasing IKAP protein expressionin a cell (e.g., ex vivo or in vivo), the method comprising contactingthe cell with a therapeutically effective amount of a compound providedherein, (i.e., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof). In some embodiments the method is an in vitromethod. In some embodiments, the method is an in vivo method. In someembodiments, the amount IKAP protein expression is increased in a cellselected from the group consisting of a lung cell, a muscle cell, aliver cell, a heart cell, a brain cell, a kidney cell, and a nerve cell(e.g., a sciatic nerve cell or a trigeminal nerve cell), or anycombination thereof. In some embodiments thereof, the amount of IKAPprotein expression is increased in the plasma.

Also provided herein are methods for increasing IKAP protein level in apatient in need thereof, the method comprising administering aneffective amount of a compound provide herein, (i.e., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof), to thepatient. For example, such methods include increasing IKAP protein levelin serum samples from the patient. Further provided herein are methodsfor increasing the mean percentage of IKAP protein level in a patient inneed thereof, the method comprising administering an effective amount ofa compound provided herein (i.e., a compound of Formula (I), or apharmaceutically acceptable salt thereof, to the patient.

Also provided herein are methods for increasing IKAP protein level in acell (e.g., ex vivo or in vivo), the method comprising contacting thecell with a therapeutically effective amount of a compound providedherein, (i.e., a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof). In some embodiments the method is an in vitromethod. In some embodiments, the method is an in vivo method. In someembodiments, the amount IKAP protein level is increased in a cellselected from the group consisting of a lung cell, a muscle cell, aliver cell, a heart cell, a brain cell, a kidney cell, and a nerve cell(e.g., a sciatic nerve cell or a trigeminal nerve cell), or anycombination thereof. In some embodiments thereof, the amount of IKAPprotein level is increased in the plasma.

Also provided herein are methods for increasing WT IKBKAP mRNA in apatient in need thereof, the method comprising administering aneffective amount of a compound provide herein, (i.e., a compound ofFormula (I), or a pharmaceutically acceptable salt thereof), to thepatient. For example, such methods include increasing WT IKBKAP mRNAconcentration in serum samples from the patient. Further provided hereinare methods for increasing the mean percentage exon inclusion (i.e. thepercentage of correctly spliced or WT IKBKAP mRNA) in a patient in needthereof, the method comprising administering an effective amount of acompound provided herein (i.e., a compound of Formula (I), or apharmaceutically acceptable salt thereof, to the patient.

In some embodiments, WT IKBKAP mRNA can be measured in the serum, forexample, in blood samples obtained from the patient prior toadministration of a compound as provided herein and in blood samplesobtained from the patient following administration of a compound asprovided herein. In some embodiments, the blood samples obtained fromthe patient following administration are obtained after one day, twodays, three days, four days, five days, six days, seven days, eightdays, nine days, ten days, fourteen days, twenty-one days, twenty-eightdays, and/or thirty days of administration of the compound as providedherein. See, for example, F. B. Axelrod et al., Pediatr Res (2011)70(5): 480-483; and R. S. Shetty et al., Human Molecular Genetics (2011)20(21): 4093-4101, both of which are incorporated by reference in theirentirety.

Further provided herein is a method of increasing WT IKBKAP mRNA in acell, the method comprising contacting the cell with a therapeuticallyeffective amount of a compound provided herein (i.e., a compound ofFormula (I)). The amount of WT IKBKAP mRNA in the treated cell isincreased relative to a cell in a subject not administered a compoundprovided herein. The method of increasing the amount of WT IKBKAP mRNAin a cell may be performed by contacting the cell with a compoundprovided herein (i.e., a compound of Formula (I), or a pharmaceuticallyacceptable salt form thereof), in vitro, thereby increasing the amountWT IKBKAP mRNA of a cell in vitro. Uses of such an in vitro method ofincreasing the amount of WT IKBKAP mRNA include, but are not limited to,use in a screening assay (for example, wherein a compound providedherein is used as a positive control or standard compared to a compoundor compounds of unknown activity or potency in increasing the amount WTIKBKAP mRNA). In some embodiments, the amount of WT IKBKAP mRNA isincreased in a cell selected from the group consisting of a lung cell, amuscle cell, a liver cell, a heart cell, a brain cell, a kidney cell,and a nerve cell (e.g., a sciatic nerve cell or a trigeminal nervecell), or any combination thereof. In some embodiments thereof, theamount of WT IKBKAP mRNA is increased in the plasma.

The method of increasing WT IKBKAP mRNA in a cell may be performed, forexample, by contacting a cell, (e.g., a lung cell, a muscle cell, aliver cell, a heart cell, a brain cell, a kidney cell, or a nerve cell),with a compound provided herein (i.e. a compound of Formula (I), or apharmaceutically acceptable salt thereof), in vivo, thereby increasingthe amount of WT IKBKAP mRNA in a subject in vivo. The contacting isachieved by causing a compound provided herein, or a pharmaceuticallyacceptable salt form thereof, to be present in a subject in an amounteffective to achieve an increase in the amount of WT IKBKAP mRNA. Thismay be achieved, for example, by administering an effective amount of acompound provided herein, or a pharmaceutically acceptable salt formthereof, to a subject. Uses of such an in vivo method of increasing theamount of WT IKBKAP mRNA include, but are not limited to, use in methodsof treating a disease or condition, wherein an increase in the amount ofWT IKBKAP mRNA is beneficial. In some embodiments thereof, the amount ofWT IKBKAP mRNA is increased in a cell selected from the group consistingof a lung cell, a muscle cell, a liver cell, a heart cell, a brain cell,a kidney cell, and a nerve cell (e.g., a sciatic nerve cell or atrigeminal nerve cell), or any combination thereof, for example in apatient suffering from a disease or disorder provided herein (e.g.,familial dysautonomia or neurofibromatosis 1). The method is preferablyperformed by administering an effective amount of a compound providedherein, or a pharmaceutically acceptable salt form thereof, to a subjectwho is suffering from familial dysautonomia or neurofibromatosis 1.

Combination Therapies

In some embodiments, one or more of the compounds provided herein may beadministered to a subject in need thereof in combination with at leastone additional pharmaceutical agent. In some embodiments, the additionalpharmaceutical agent is a compound provided herein (e.g., a compound ofFormula (I)).

Additional examples of suitable additional pharmaceutical agents for usein combination with the compounds of the present application fortreatment of the diseases provided herein include, but are not limitedto, antioxidants, anti-inflammatory agents, steroids,immunosuppressants, or other agents such as therapeutic antibodies. Insome embodiments, the compounds provided herein may be administered to asubject in need thereof in combination with at least one additionalpharmaceutical agent for the treatment of familial dysautonomia. In someembodiments, the additional pharmaceutical agent is phosphatidylserine.

Pharmaceutical Compositions and Formulations

When employed as pharmaceuticals, the compounds provided herein can beadministered in the form of pharmaceutical compositions; thus, themethods described herein can include administering the pharmaceuticalcompositions. These compositions can be prepared as described herein orelsewhere, and can be administered by a variety of routes, dependingupon whether local or systemic treatment is desired and upon the area tobe treated. Administration may be pulmonary (e.g., by inhalation orinsufflation of powders or aerosols, including by nebulizer;intratracheal or intranasal), oral, or parenteral. Parenteraladministration may include, but is not limited to intravenous,intraarterial, subcutaneous, intraperitoneal, intramuscular injection orinfusion; or intracranial, (e.g., intrathecal, intraocular, orintraventricular) administration. Parenteral administration can be inthe form of a single bolus dose, or may be, for example, by a continuousperfusion pump. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable. Insome embodiments, the compounds provided herein are suitable for oraland parenteral administration. In some embodiments, the compoundsprovided herein are suitable for oral administration. In someembodiments, the compounds provided herein are suitable for parenteraladministration. In some embodiments, the compounds provided herein aresuitable for intravenous administration. In some embodiments, thecompounds provided herein are suitable for transdermal administration(e.g., administration using a patch or microneedle). Pharmaceuticalcompositions for topical administration may include transdermal patches(e.g., normal or electrostimulated), ointments, lotions, creams, gels,drops, suppositories, sprays, liquids and powders. Conventionalpharmaceutical carriers, aqueous, powder or oily bases, thickeners andthe like may be necessary or desirable.

Also provided are pharmaceutical compositions which contain, as theactive ingredient, a compound provided herein (e.g., a compound ofFormula (I)), or a pharmaceutically acceptable salt thereof, incombination with one or more pharmaceutically acceptable carriers(excipients). In making the compositions provided herein, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include, without limitation,lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water,syrup, and methyl cellulose. The formulations can additionally include,without limitation, lubricating agents such as talc, magnesium stearate,and mineral oil; wetting agents; emulsifying and suspending agents;preserving agents such as methyl- and propylhydroxy-benzoates;sweetening agents; flavoring agents, or combinations thereof.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered and the schedule of administration will usually bedetermined by a physician, according to the relevant circumstances,including the condition to be treated, the chosen route ofadministration, the actual compound administered, the age, weight, andresponse of the individual subject, the severity of the subject'ssymptoms, and the like.

Kits

Also provided herein are kits including a compound provided herein, moreparticularly to a compound of Formula (I) or Formula (II), or apharmaceutically acceptable salt thereof. In some embodiments, a kit caninclude one or more delivery systems, e.g., for a compound providedherein, or a pharmaceutically acceptable salt thereof, and directionsfor use of the kit (e.g., instructions for treating a subject). In someembodiments, a kit can include a compound provided herein, or apharmaceutically acceptable salt thereof, and one or more additionalagents as provided herein.

In some embodiments, the compound is selected from the group ofcompounds provided in Table A, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound is selected from the group ofcompounds provided in Table A-2, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound is selected from the group ofcompounds provided in Table A-3, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound is selected from the group ofcompounds provided in Table B, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound is selected from the group ofcompounds provided in Table B-2, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound is selected from the group ofcompounds provided in Table B-3, or a pharmaceutically acceptable saltthereof. In some embodiments, the compound is selected from the group ofcompounds provided in Table C, or a pharmaceutically acceptable saltthereof.

In some embodiments, the kit can include one or more compounds oradditional pharmaceutical agents as provided herein, or apharmaceutically acceptable salt thereof, and a label that indicatesthat the contents are to be administered to a subject resistant to astandard of care agent or adjuvant used for the treatment of familialdysautonomia or neurofibromatosis 1. In some embodiments, the additionalpharmaceutical agent is phosphatidylserine. In another embodiment, thekit can include a compound provided herein, or a pharmaceuticallyacceptable salt thereof, and a label that indicates that the contentsare to be administered to a subject with cells expressing abnormal WTIKBKAP mRNA splicing. In another embodiment, the kit can include one ormore compounds or additional pharmaceutical agents as provided herein,or a pharmaceutically acceptable salt thereof, and a label thatindicates that the contents are to be administered to a subject having adisease of the central nervous system resulting from abnormal mRNAsplicing. In another embodiment, the kit can include one or morecompounds or additional pharmaceutical agents as provided herein, or apharmaceutically acceptable salt thereof, and a label that indicatesthat the contents are to be administered to a subject having familialdysautonomia or neurofibromatosis 1. In some embodiments, a kit caninclude one or more compounds as provided herein, or a pharmaceuticallyacceptable salt thereof, and a label that indicates that the contentsare to be administered with one or more additional pharmaceutical agentsas provided herein.

EXAMPLES

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

General Methods

All reactions were performed under a dry atmosphere of nitrogen unlessotherwise specified. Indicated reaction temperatures refer to thereaction bath, while room temperature (rt) is noted as 25° C. Commercialgrade reagents and anhydrous solvents were used as received from vendorsand no attempts were made to purify or dry these components further.Removal of solvents under reduced pressure was accomplished with a Buchirotary evaporator at approximately 28 mm Hg pressure using aTeflon-linked KNF vacuum pump. Thin layer chromatography was performedusing 1″×3″ AnalTech No. 02521 silica gel plates with fluorescentindicator. Visualization of TLC plates was made by observation witheither short wave UV light (254 nm lamp), 10% phosphomolybdic acid inethanol or in iodine vapors. Preparative thin layer chromatography wasperformed using Analtech, 20×20 cm, 1000 micron preparative TLC plates.Flash column chromatography was carried out using a Teledyne IscoCombiFlash Companion Unit with RediSep® Rf silica gel columns. Ifneeded, products were purified by reverse phase chromatography, using aTeledyne Isco CombiFlash Companion Unit with RediSep® Gold C18 reversephase column. Proton NMR spectra were obtained either on 300 MHz BrukerNuclear Magnetic Resonance Spectrometer or 500 MHz Bruker NuclearMagnetic Resonance Spectrometer and chemical shifts Bruker NuclearMagnetic Resonance Spectrometer and chemical shifts (δ are reported inparts per million (ppm) and coupling constant (J) values are given inHz, with the following spectral pattern designations: s, singlet; d,doublet; t, triplet, q, quartet; dd, doublet of doublets; m, multiplet;br, broad. Tetramethylsilane was used as an internal reference. Meltingpoints are uncorrected and were obtained using a MEL-TEMP Electrothermalmelting point apparatus. Mass spectroscopic analyses were performedusing positive mode electron spray ionization (ESI) on a Varian ProStarLC-MS with a 1200 L quadrapole mass spectrometer. High pressure liquidchromatography (HPLC) purity analysis was performed using a Varian ProStar HPLC system with a binary solvent system A and B using a gradientelusion [A, H₂O with 0.1% trifluoroacetic acid (TFA); B, CH₃CN with 0.1%TFA] and flow rate=1 mL/min, with UV detection at 254 nm. All finalcompounds were purified to ≥95% purity by the Varian Pro Star HPLCsystem using the following methods:

-   -   A) Phenomenex Luna C18(2) column (4.60×250 mm); mobile phase,        A=H₂O with 0.1% TFA and B=CH₃CN with 0.1% TFA; gradient: 10-100%        B (0.0-20.0 min); UV detection at 254 nm.    -   B) Phenomenex Luna C18(2) column (4.60×250 mm); mobile phase,        A=H₂O with 0.1% TFA and B=CH₃CN with 0.1% TFA; gradient: 10-95%        B (0.0-10.0 min); hold 95% B (6.0 min); UV detection at 254 nm.

Intermediate 1. 2-(4,6-Dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol

A solution of 2,4,6-trichloropyrimidine-5-carboxaldehyde (414 mg, 1.96mmol) in EtOH (14 mL) at −78° C. was treated with a solution of(2-hydroxyethyl)hydrazine (0.15 mL, 2.2 mmol) and TEA (0.57 mL, 4.1mmol) in EtOH (2 mL) via dropwise addition and stirred for 30 min. Themixture was then allowed to warm to 0° C. while stirring for anadditional 30 min, and then 2N HCl was added dropwise until pH=6. Thesolvents were removed by rotary evaporation and the crude residue waspurified by chromatography on silica gel (gradient 0-100% EtOAc inhexanes) to afford the title compound (262 mg, 57%): ¹H NMR (300 MHz,CDCl₃) δ 8.57 (s, 1H), 4.87 (t, J=5.4 Hz, 1H), 4.48-4.43 (m, 2H),3.87-3.80 (m, 2H).

Intermediate 2.4,6-Dichloro-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine

A solution of 2-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol(100.4 mg, 0.431 mmol) in dichloromethane (2 mL) at −78° C. was treatedwith Deoxo-Fluor (0.09 mL, 0.49 mmol) via dropwise addition and stirredfor 30 min. The mixture was then allowed to warm to room temperaturewhile stirring for an additional 30 min, then water (5 mL) and sat. aq.NaHCO₃ (3 mL) were added. The layers were separated, and the aqueouslayer was extracted with dichloromethane (2×10 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated to dryness.The crude residue was purified by chromatography on silica gel (gradient0-10% methanol in DCM) to afford the title compound (18.3 mg, 18%) as anoff-white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (s, 1H), 4.95 (t,J=4.4 Hz, 1H), 4.82-4.75 (m, 2H), 4.73-4.69 (m, 2H).

Intermediate 3. Ethyl N-((1H-1,2,4-triazol-5-yl)carbamothioyl)carbamate

A solution of 3-amino-1,2,4-triazole (521 mg, 6.20 mmol) in DMF (7 mL)at 10° C. was treated with ethoxycarbonyl isothiocyanate (0.70 mL, 6.19mmol) via dropwise addition, and the mixture was allowed to roomtemperature while stirring for 16 h. Water (75 mL) was added, and themixture was extracted with EtOAc (3×50 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo toafford the title compound (960 mg, 72%) as a yellow solid: ¹H NMR (500MHz, DMSO-d₆) δ 13.99 (br s, 1H), 12.10-11.71 (br d, 1H), 11.45 (br s,1H), 8.53 (s, 1H), 4.27-4.16 (m, 2H), 1.25 (t, J=7.1 Hz, 3H).

Intermediate 4. Disodium5-sulfido-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-olate

A solution of ethyl N-((1H-1,2,4-triazol-5-yl)carbamothioyl)carbamate(960 mg, 4.46 mmol) in EtOH (18 mL) was treated with aqueous NaOH (2N,5.0 mL, 10 mmol), warmed to reflux for 30 min, then cooled to roomtemperature. The precipitated solid was collected on a fritted funneland rinsed with cold EtOH (2×20 mL), then dried under vacuum at 60° C.for 1 h to afford the title compound (913 mg, 96%) as an off-whitesolid: ¹H NMR (500 MHz, DMSO-d₆) δ 7.57 (s, 1H).

Intermediate 5.5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one

A solution of 5-sulfido-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-olatedisodium salt (721 mg, 3.38 mmol) in water (21 mL) was treated with aq.HCl solution (2N, 7 mL, 14 mmol) and stirred for 10 min. Theprecipitated solid was collected on a fritted funnel dried under vacuumat 60° C. for 1 h to afford the title compound (480 mg, 84%) as anoff-white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 14.23 (br s, 1H), 13.04 (brs, 1H), 8.17 (s, 1H).

Intermediate 6.5-(methylthio)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(6H)-one

A solution of5-thioxo-5,6-dihydro-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(4H)-one (149mg, 0.881 mmol) in THF (0.6 mL) was treated with sodium methoxidesolution (0.5 M in methanol, 1.85 mL, 0.925 mmol) and stirred for 2 min.Iodomethane solution (1.0 M in THF, 0.92 mL, 0.92 mmol) was added andthe mixture was stirred for 16 h. The solvents were removed by rotaryevaporation, and the residue was suspended in water (5 mL) and filtered.The collected solid was washed with additional water (5 mL) and driedunder vacuum at 60° C. for 1 h to afford the title compound (80.5 mg,50%) as a white solid: ¹H NMR (500 MHz, DMSO-d₆) δ 13.40 (br s, 1H),8.31 (s, 1H), 2.57 (s, 3H).

Intermediate 7. Triethyl ethane-1,1,2-tricarboxylate

Diethyl malonate (20 mL, 132 mmol) was added dropwise to a solution ofethanolic sodium ethoxide (21% by weight, approx. 2.65 M, 50 mL, 133mmol) in EtOH (80 mL) at 0° C. and stirred for 30 min. Ethylchloroacetate (14 mL, 131 mmol) was added dropwise, the mixture washeated to reflux for 3.25 h and then cooled to room temperature. Allvolatiles were removed by rotary evaporation, the residue waspartitioned between EtOAc (400 mL) and water (300 mL), and the layerswere separated. The organic layer was washed with sat. aq. NaCl solution(200 mL), dried over Na₂SO₄, filtered and concentrated in vacuo toafford the title compound (30.5 g, 94% crude) as an orange oil: ¹H NMR(300 MHz, CDCl₃) δ 4.25-4.14 (m, 6H), 3.83 (t, J=7.3 Hz, 1H), 2.92 (d,J=7.4 Hz, 2H), 1.31-1.23 (m, 9H).

Intermediate 8. Ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)acetate

A mixture of triethyl ethane-1,1,2-tricarboxylate (30.5 g, 124 mmol),urea (7.44 g, 124 mmol) and ethanolic sodium ethoxide solution (21% byweight, approx. 2.65 M, 73 mL, 194 mmol) in EtOH (180 mL) was heated toreflux for 17 h, then cooled to room temperature. All volatiles wereremoved by rotary evaporation, and water (400 mL) was added. Aqueous 2NHCl was added to adjust the solution to pH=3, and the mixture wasextracted with EtOAc (3×150 mL). The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle compound (8.0 g, 30%) as a tan solid: ¹H NMR (300 MHz, CDCl₃) δ8.28 (br s, 1H), 8.18 (br s, 1H), 4.80 (br s, 1H), 4.18-4.08 (m, 2H),1.30-1.25 (m, 3H).

Intermediate 9. Ethyl 2-(2,4,6-trichloropyrimidin-5-yl)acetate

A mixture of ethyl 2-(2,4,6-trioxohexahydropyrimidin-5-yl)acetate (8.0g, 37.4 mmol) and DIPEA (10 mL, 57 mmol) in phosphorous(V) oxychloride(50 mL) was heated to reflux for 3 h, then carefully poured onto icewater (500 g) and stirred for 1 h. Potassium carbonate was added toadjust pH to 3, and the mixture was extracted with EtOAc (3×200 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by chromatographyon silica gel (gradient 0-50% EtOAc in hexanes) to afford the titlecompound (3.20 g, 32%) as an off white solid: ¹H NMR (300 MHz, CDCl₃) δ4.23 (q, J=7.1 Hz, 2H), 3.94 (s, 2H), 1.29 (t, J=7.1 Hz, 3H).

Intermediate 10. Ethyl 2-(4-amino-2,6-dichloropyrimidin-5-yl)acetate

A solution of ethyl 2-(2,4,6-trichloropyrimidin-5-yl)acetate (880 mg,3.27 mmol) in DMF (15 mL) was treated with sodium azide (213 mg, 3.28mmol) and stirred at room temperature for 2 h. Water (200 mL) was added,and the mixture was extracted with EtOAc (3×50 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude residue (1.02 g, quant.) was dissolved in THF (7 mL) and water(3.5 mL), then treated with trimethylphosphine solution (1.0 M in THF,3.5 mL, 3.5 mmol) and stirred at room temperature for 20 h. EtOAc (75mL) was added, and the organic layer was washed with water (2×20 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by chromatography on silica gel (gradient 0-80% EtOAc inhexanes) to afford the title compound (517 mg, 64% over 2 steps) as awhite solid: ¹H NMR (300 MHz, CDCl₃) δ 5.73 (br s, 2H), 4.20 (q, J=7.1Hz, 2H), 3.66 (s, 2H), 1.29 (t, J=7.1 Hz, 3H).

Intermediate 11. 2,4-dichloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

A solution of ethyl 2-(4-amino-2,6-dichloropyrimidin-5-yl)acetate (197mg, 0.788 mmol) in DMF (8 mL) at 0° C. was treated with sodium hydride(60% dispersion in mineral oil, 70 mg, 1.75 mmol) and stirred for 40min. Aqueous lithium chloride solution (5% solution, 40 mL) was added,and the mixture was extracted with EtOAc (3×50 mL). The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was purified by chromatography on silica gel (gradient 0-10%methanol in DCM) to afford the title compound (46 mg, 29%) as a yellowsolid: ¹H NMR (300 MHz, DMSO-d₆) δ 12.02 (br s, 1H), 3.65 (s, 2H).

Intermediate 12. 2,6-Dichloro-7-methyl-7H-purine

To a solution of 2,6-dichloro-7H-purine (1.05 g, 5.56 mmol) in THF (8mL) at 0° C. under nitrogen was added NaH (60% in mineral oil, 525 mg,13.1 mmol) in one portion and, after stirring for 30 min at 0° C.,iodomethane (0.38 mL, 6.12 mmol) was added. The mixture was stirred at0° C. for 1 h and then at room temperature for 16 h. After this time,the reaction mixture was diluted with EtOAc and washed with water andbrine. The organic layer was concentrated under reduced pressure and theresidue obtained was purified by column chromatography (silica, 0-30%EtOAc in CH₂Cl₂) to provide isomers 2,6-dichloro-9-methyl-9H-purine (491mg, 43%) and 2,6-dichloro-7-methyl-7H-purine (312 mg, 28%): ESI MS (M+H)203; 2,6-dichloro-9-methyl-9H-purine ¹H NMR (300 MHz, DMSO-d₆) δ 8.69(s, 1H), 3.83 (s, 3H) and 2,6-dichloro-7-methyl-7H-purine ¹H NMR (300MHz, DMSO-d₆) δ 8.81 (s, 1H), 4.07 (s, 3H).

Intermediate 13. 8-Bromo-2,6-dichloro-7-methyl-7H-purine

A suspension of 2,6-dichloro-7-methyl-7H-purine (250 mg, 1.23 mmol) inTHF (10 mL) under nitrogen was cooled to −78° C., and then LDA (2.0 M inTHF/heptane/ethylbenzene, 1.80 mL, 3.60 mmol) was added to obtain a darksolution, which was stirred for 15 min. After this time, a solution of1,2-dibromo-1,1,2,2-tetrachloroethane (1.20 g, 3.69 mmol) in THF (2 mL)was added and the reaction mixture was stirred at −78° C. for 1 h. Asaturated solution of NH₄Cl was added, and then the mixture wasextracted with EtOAc. The organic layer was dried over sodium sulfateand then concentrated. The residue was purified by column chromatography(silica, 0-3% MeOH in CH₂Cl₂) to provide8-bromo-2,6-dichloro-7-methyl-7H-purine (135 mg, 39%): ESI MS (M+H) 281;¹H NMR (500 MHz, DMSO-d₆) δ 4.02 (s, 3H).

Intermediate 14. 2,6-Dichloro-7-methyl-8-propoxy-7H-purine

Sodium hydride (60% in mineral oil, 20 mg, 0.50 mmol) was carefullyadded to n-propanol (35 mg, 0.58 mmol) to obtain a solution which wasadded to a solution of 8-bromo-2,6-dichloro-7-methyl-7H-purine (125 mg,0.44 mmol) in THF (2 mL). The resulting mixture was stirred at roomtemperature for 1.5 h. After this time the mixture was concentrated andthe residue purified by column chromatography (silica, 0-10% EtOAc inCH₂Cl₂) to provide 2,6-dichloro-7-methyl-8-propoxy-7H-purine (68 mg,59%): ESI MS (M+H) 261; ¹H NMR (500 MHz, DMSO-d₆) δ 4.58 (t, J=6.5 Hz,2H), 3.74 (s, 3H), 1.87-1.81 (m, 2H), 1.01 (t, J=7.4 Hz, 3H).

Intermediate 15. 2-Bromo-5,7-dichlorothiazolo[5,4-d]pyrimidine

A solution of 2-bromo-5,7-dichlorothiazolo[5,4-d]pyrimidine (180 mg,0.87 mmol) in THF (8 mL) under nitrogen was cooled to −78° C. LDA (2.0 Min THF/heptane/ethylbenzene, 1.30 mL, 2.60 mmol) was added slowly andthe mixture was stirred for 10 min. After this time, a solution of1,2-dibromo-1,1,2,2-tetrachloroethane (850 mg, 2.61 mmol) in THF (2 mL)was added and the reaction mixture was stirred at −78° C. for 1.5 h. Asaturated solution of NH₄Cl was added, and then the mixture wasextracted with EtOAc. The organic layer was dried over sodium sulfateand then concentrated. The residue was purified by column chromatography(silica, 0-20% EtOAc, hexanes) to provide2-bromo-5,7-dichlorothiazolo[5,4-d]pyrimidine (134 mg, 54%): ESI MS(M+H) 284.

Intermediate 16.(E)-6-Chloro-5-((4-chlorophenyl)diazenyl)pyrimidine-2,4-diamine

To a suspension of 4-chloroaniline (1.28 g, 10 mmol) in water (9 mL) wasadded concentrated HCl (2.75 mL, 33 mmol) and then stirred for 10minutes. A solution of NaNO₂ (725 mg, 10.5 mmol) in water (9 mL) wasadded dropwise at 0° C. resulting in a clear solution. In a separateflask, acetic acid (45 mL, 81 mmol) and NaOAc (18 g, 216 mmol) wereadded to a suspension of 6-chloropyrimidine-2,4-diamine (1.3 g, 9 mmol)in water (45 mL). The clear solution from above was then added dropwiseto the suspension and the reaction was allowed to stir overnight at roomtemperature. The resulting solid that formed was isolated by suctionfiltration to afford the title compound (3 g, >100%): ¹H NMR (300 MHz,DMSO-d₆) δ 9.26 (s, 1H), 8.17 (s, 1H), 7.81 (d, J=8.7 Hz, 2H), 7.54 (d,J=8.7 Hz, 2H), 7.34 (br s, 2H).

Intermediate 17. 6-Chloropyrimidine-2,4,5-triamine

To a suspension of(E)-6-Chloro-5-((4-chlorophenyl)diazenyl)pyrimidine-2,4-diamine (2.2 g,7 mmol) in THF (70 mL) was added acetic acid (10 mL) followed by Zn dust(3.3 g, 50 mmol) at 0° C. The reaction was stirred for 30 minutes thenfiltered through a pad of Celite. The filtrate was concentrated underreduced pressure and the residue was purified by silica gelchromatography (0-30% 90:9:1 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OHin Cl₂Cl₂) to afford the title compound (300 mg, 27%): ¹H NMR (500 MHz,DMSO-d₆) δ 6.33 (s, 2H), 5.48 (s, 2H), 3.88 (s, 2H).

Intermediate 18: 7-Chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine

To a solution of 6-chloropyrimidine-2,4,5-triamine (290 mg, 1.8 mmol) inwater (25 mL) and acetic acid (6 mL) was added a solution of NaNO₂ (150mg, 2.16 mmol) in water (3 mL) at 0° C. After 1 h at 0° C., aprecipitate formed which was isolated by suction filtration washing withwater. The solid was dissolved in EtOH and concentrated under reducedpressure to afford the title compound as a gray solid (150 mg, 49%): ¹HNMR (300 MHz, DMSO-d₆) δ 15.90 (s, 1H), 7.49 (s, 2H).

Example 1. General Procedure A

A mixture of the desired pyrrolopyrimidine or purine i-A (1 equiv),desired aminomethyl heterocycle or benzylamine ii-A (1.1 equiv), andtriethylamine (NEt₃) or diisopropylethylamine (DIPEA) (1.5-3.5 equiv) ina suitable solvent (e.g., 1,4-dioxane, THF, EtOH, n-BuOH) was stirred at50-150° C. in a reaction flask or sealed tube until the reaction wascomplete by LC-MS and/or TLC analysis. Following completion, thereaction mixture was cooled to room temperature, diluted with CH₂Cl₂ andwashed with saturated NaHCO₃ solution. The organic extract was driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by silica gel chromatography (typicaleluents included, for example, a mixture of hexanes and EtOAc, or amixture of CH₂Cl₂ and MeOH, or an 80:18:2 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired product iii-A.The product structures prepared according to General Procedure A wereconfirmed by ¹H NMR and/or by mass analysis.

Example 2. General Procedure B

A mixture of the desired chloropyrazolopyrimidine i-B (1 equiv), desiredaminomethyl heterocycle or benzylamine ii-B (1.1 equiv), andtriethylamine (NEt₃) or diisopropylethylamine (DIPEA) (1.5-3.5 equiv) ina suitable solvent (e.g. 1,4-dioxane, THF, EtOH, n-BuOH) was stirred at50-150° C. in a sealed tube until the reaction was complete by LC-MSand/or TLC analysis. Following completion, the reaction mixture wascooled to room temperature, diluted with CH₂Cl₂, and washed withsaturated NaHCO₃ solution. The organic extract was dried over Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by silica gel chromatography (typical eluents included, forexample, a mixture of hexanes and EtOAc, or a mixture of CH₂Cl₂ andMeOH, or an 80:18:2 mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) toafford the desired product iii-B. The product structures preparedaccording to General Procedure B were confirmed by ¹H NMR and/or by massanalysis.

Example 3. General Procedure C

Step 1. General Procedure C1 for Purine Ring Formation

A mixture of 5,6-diaminouracil sulfate salt i-C or6-chloropyrimidine-4,5-diamine (1 equiv), the desired carboxylic acid oracid chloride ii-C (1.1 equiv), POCl₃ (4 mL/100 mg of i-C), and NH₄Cl (6equiv) was stirred at 100° C. until the reaction was complete by LC-MSand/or TLC analysis. The reaction mixture was cooled to room temperatureand carefully poured over ice (caution: exothermic reaction uponaddition to water). The pH was adjusted to ˜7 with concentrated NH₄OHthen the aqueous layer was extracted with EtOAc (2×) and the combinedorganic extracts were dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography (typical eluents included, for example, a mixture ofhexanes and EtOAc, or a mixture of CH₂Cl₂ and MeOH, or an 80:18:2mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desiredproduct iii-C. The product structures prepared according to GeneralProcedure C1 were confirmed by ¹H NMR and/or by mass analysis.

Step 2. General Procedure C2 for Amine Addition

A mixture of the desired chloropurine iii-C (1 equiv), desiredaminomethyl heterocycle or benzylamine iv-C (1.1 equiv), andtriethylamine (NEt₃) or diisopropylethylamine (DIPEA) (1.5 equiv) in asuitable solvent (e.g. 1,4-dioxane; ˜0.25 M) was stirred at 50-150° C.in a sealed tube until the reaction was complete by LC-MS and/or TLCanalysis. The reaction mixture was then cooled to room temperature,diluted with CH₂Cl₂ and washed with saturated NaHCO₃ solution. Theorganic extract was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography (typical eluents included, for example, a mixture ofhexanes and EtOAc, or a mixture of CH₂Cl₂ and MeOH, or an 80:18:2mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desiredproduct v-C. The product structures prepared by General Procedure C2 wasconfirmed by ¹H NMR and/or by mass analysis.

Example 4. General Procedure D

Step 1. 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

2,6-Dichloropurine i-D (1 equiv), dihydropyran (1.05 equiv), andpara-toluenesulfonic acid (0.11 equiv) in EtOAc (˜0.5 M) were stirred at65° C. overnight. After this time, the reaction was cooled to roomtemperature and washed with saturated NaHCO₃ solution followed by brine.The solution was dried over Na₂SO₄, filtered and concentrated underreduced pressure to afford a clear residue. The resulting residue wastriturated with MeOH and the resulting white solid was collected bysuction filtration to afford ii-D as a white solid; ESI MS (M+H) 273.

Step 2. 8-bromo-2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine

To a solution of 2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purineii-D (1 equiv) in THF (˜0.1 M) was added LDA (3 equiv) at −78° C. andstirred for 20 minutes. After this time, a solution ofdibromotetrachloroethane (DBTCE, 3 equiv) in THF (˜0.4 M) was addedslowly and stirred at −78° C. for 90 minutes. The reaction was quenchedwith saturated NH₄Cl solution and diluted with EtOAc. The layers wereseparated and the organic layer was washed with brine, dried overNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue purified by silica gel chromatography (EtOAc/hexanes) to affordthe title compound iii-D. ¹H NMR (500 MHz, DMSO-d₆) 5.69 (dd, J=11.5,2.5 Hz, 1H), 4.09-4.05 (m, 1H), 3.71 (td, J=11.5, 3.5 Hz, 1H), 2.83-2.75(m, 1H), 2.02-2.00 (m, 1H), 1.96-1.93 (m, 1H), 1.78-1.69 (m, 1H),1.66-1.58 (m, 2H).

Step 3a.8-bromo-2-chloro-9-(tetrahydro-2H-pyran-2-yl)-N-(thiazol-2-ylmethyl)-9H-purin-6-amine

8-Bromo-2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1 equiv),2-(aminomethyl)thiazole dihydrochloride (1.1 equiv) and triethylamine orDIPEA (3 equiv) in 1,4-dioxane (˜0.4 M) were stirred at room temperatureovernight. The reaction mixture was then concentrated under reducedpressure and purified by silica gel chromatography (EtOAc/hexanes) toafford the title compound (iv-D(a)) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.29 (s, 1H), 7.73 (d, J=3.5 Hz, 1H), 7.60 (d, J=3.0 Hz, 1H),5.58 (dd, J=11.0, 2.0 Hz, 1H), 4.89 (d, J=6.0 Hz, 2H), 4.06 (s, 1H),3.66 (td, J=11.5, 3.5 Hz, 1H), 2.87-2.78 (m, 1H), 2.00 (s, 1H),1.90-1.85 (m, 1H), 1.74-1.55 (m, 3H).

Step 3b.8-bromo-2-chloro-N-(pyridin-4-ylmethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

8-Bromo-2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine,4-(aminomethyl)pyridine (1.1 equiv) and triethylamine or DIPEA (1.5equiv) in 1,4-dioxane (˜0.4 M) were stirred at room temperatureovernight. The reaction mixture was then concentrated under reducedpressure and purified by silica gel chromatography (EtOAc/hexanes) toafford the title compound (iv-D(b)) as a yellow solid. ¹H NMR (500 MHz,CDCl₃) δ 8.57 (dd, J=4.5, 1.5 Hz, 2H), 7.253-7.250 (m, 2H), 6.08 (br s,1H), 5.67 (dd, J=11.5, 2.5 Hz, 1H), 4.83 (br s, 2H), 4.19-4.16 (m, 1H),3.71 (td, J=12.0, 2.5 Hz, 1H), 2.96-2.90 (m, 1H), 2.12-2.09 (m, 1H),1.86-1.59 (m, 4H).

Step 3c.8-bromo-2-chloro-N-(pyrimidin-4-ylmethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

8-Bromo-2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1 equiv),4-(aminomethyl)pyrimidine hydrochloride (1.1 equiv) and triethylamine orDIPEA (2 equiv) in 1,4-dioxane (˜0.4 M) were stirred at room temperatureovernight. The reaction mixture was then concentrated under reducedpressure and purified by silica gel chromatography (EtOAc/hexanes) toafford the title compound (iv-D(c)) as a yellow solid. ¹H NMR (300 MHz,CDCl₃) δ 9.19 (d, J=1.5 Hz, 1H), 8.70 (d, J=5.4 Hz, 1H), 7.34 (d, J=5.7Hz, 1H), 6.94 (br s, 1H), 5.68 (dd, J=11.4, 2.4 Hz, 1H), 4.90 (br s,2H), 4.20-4.16 (m, 1H), 3.72 (td, J=12.0, 2.7 Hz, 1H), 3.00-2.88 (m,1H), 2.13-2.04 (m, 1H), 1.87-1.59 (m, 4H).

Step 3d.8-bromo-2-chloro-N-(furan-2-ylmethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine

8-Bromo-2,6-dichloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (1 equiv),furfurylamine (1.1 equiv), and triethylamine or DIPEA (2 equiv) in1,4-dioxane (˜0.4 M) were stirred at room temperature overnight. Thereaction mixture was then concentrated under reduced pressure andpurified by silica gel chromatography (EtOAc/hexanes) to afford thetitle compound (iv-D(d)) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆)8.95 (s, 1H), 7.56 (s, 1H), 6.38-6.37 (m, 1H), 6.26 (d, J=2.5 Hz, 1H),5.56 (d, J=10 Hz, 1H), 4.60 (d, J=5.5 Hz, 2H), 4.06-4.03 (m, 1H), 3.66(td, J=11.5, 3.5 Hz, 1H), 2.85-2.78 (m, 1H), 1.98 (d, J=13.5 Hz, 1H),1.88-1.85 (m, 1H), 1.71-1.67 (m, 1H), 1.59-1.55 (m, 2H).

Step 4a. General Procedure D1 for Formation of C8-Alkoxy Purines

To a mixture of the desired intermediate iv-D(a-d) (1 equiv) and thedesired alkyl alcohol (excess, >10 equiv) in a microwave vial was addedpotassium tert-butoxide (2-10 equiv). 1,4-Dioxane or THF (˜0.3 M) can beused as a solvent, if necessary. The reaction vial was sealed and heatedat 60-80° C. until the reaction was complete by LC-MS and/or TLCanalysis. The mixture was then diluted with EtOAc, washed with waterthen brine. The organic layer was dried over Na₂SO₄, filtered,concentrated under reduced pressure, and purified by silica gelchromatography (typical eluents included either a mixture of hexanes andEtOAc or a mixture of CH₂Cl₂ and MeOH or an 80:18:2 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired product v-D. Theproduct structures prepared according to General Procedure D1 wereconfirmed by ¹H NMR and/or by mass analysis.

Step 4b. General Procedure D2 for Formation of C8-Alkoxy Purines

To a mixture of the desired intermediate iv-D(a-d) (1 equiv) and thedesired alkyl alcohol (2->10 equiv) in a microwave vial was added sodiumhydride (2 equiv). 1,4-Dioxane or THF (˜0.3 M) can be used as a solvent,if necessary. The reaction vial was sealed and heated at 85° C. untilthe reaction was complete by LC-MS and/or TLC analysis. The mixture wasthen diluted with CH₂Cl₂, washed with saturated NH₄Cl, and thenextracted with CH₂Cl₂. The organic layers were washed with brine, driedover Na₂SO₄, filtered, concentrated under reduced pressure, and purifiedby silica gel chromatography (typical eluents included either a mixtureof hexanes and EtOAc or a mixture of CH₂Cl₂ and MeOH or an 80:18:2mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desiredproduct v-D. The product structures prepared according to GeneralProcedure D2 were confirmed by ¹H NMR and/or by mass analysis.

Step 4c. General Procedure D3 for Formation of C8-Alkoxy Purines

To a mixture of desired intermediate iv-D(a-d) (1 equiv) and the desiredalkyl alcohol (20 equiv) in 1,4-dioxane (˜0.4 M) was added 2 N NaOH (1mL). The reaction was heated at 85° C. until the reaction was completeby LC-MS and/or TLC analysis. The mixture was then diluted with CH₂Cl₂,washed with saturated NH₄Cl, and then extracted with CH₂Cl₂. The organiclayers were washed with brine, dried over Na₂SO₄, filtered, concentratedunder reduced pressure, and purified by silica gel chromatography(typical eluents included either a mixture of hexanes and EtOAc or amixture of CH₂Cl₂ and MeOH or an 80:18:2 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired product v-D. Theproduct structures prepared according to General Procedure D3 wereconfirmed by ¹H NMR and/or by mass analysis.

Step 5. General Procedure D4 for THP Deprotection

To a solution of THP protected alkoxy purine v-D (1 equiv) in MeOH(˜0.07 M) was added TFA (excess, ≥20 equiv) at 0° C. The reactionmixture was then heated at 45-70° C. until the reaction was complete byLC-MS and/or TLC analysis. The mixture was concentrated under reducedpressure then diluted with CH₂Cl₂ and washed with saturated NaHCO₃solution. The aqueous layer was extracted with CH₂Cl₂, and the combinedorganic layers were dried over Na₂SO₄, filtered, concentrated underreduced pressure and purified by silica gel chromatography (typicaleluents included either a mixture of hexanes and EtOAc or a mixture ofCH₂Cl₂ and MeOH or an 80:18:2 mixture of CH₂Cl₂/CH₃OH/concentratedNH₄OH) to afford the desired product vi-D. The product structuresprepared according to General Procedure D4 were confirmed by ¹H NMRand/or by mass analysis.

Example 5. General Procedure E

Step 1. General Procedure E1 for Formation of C8-Alkoxy Purines

A mixture of intermediate i-E (1 equiv) and the desired amine ii-E(excess), in solvent (typically NMP, DMF, or THF), was stirred at 50° C.until the reaction was complete by LC-MS and/or TLC analysis. Themixture was then diluted with CH₂Cl₂, washed with saturated NH₄Clsolution, and then the aqueous layer was extracted with CH₂Cl₂. Thecombined organic layers were washed with brine, dried over Na₂SO₄,filtered, concentrated under reduced pressure, and purified by silicagel chromatography (typical eluents included, for example, a mixture ofhexanes and EtOAc, or a mixture of CH₂Cl₂ and MeOH, or an 80:18:2mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH).

Step 2. General Procedure E2 for THP Deprotection

To a solution of THP protected amino purine iii-E (1 equiv) in MeOH(˜0.05 M) was added TFA (excess, ≥20 equiv) at 0° C. The reactionmixture stirred was then heated at 65° C. until the reaction wascomplete by LC-MS and/or TLC analysis. The mixture was concentratedunder reduced pressure then diluted with CH₂Cl₂ and washed withsaturated NaHCO₃ solution. The aqueous layer was extracted with CH₂Cl₂,and the combined organic layers were dried over Na₂SO₄, filtered,concentrated under reduced pressure and purified by silica gelchromatography to afford the desired product iv-E (typical eluentsincluded, for example, a mixture of hexanes and EtOAc, or a mixture ofCH₂Cl₂ and MeOH, or an 80:18:2 mixture of CH₂Cl₂/CH₃OH/concentratedNH₄OH).

Example 6. General Procedure F

A mixture of the desired chlorothiazolopyrimidines i-F (1 equiv),desired aminomethyl heterocycle or benzylamine ii-F (1.1 equiv), andtriethylamine (NEt₃) (1.5 equiv) in 1,4-dioxane (˜0.1 M) was stirred atroom temperature until the reaction was complete by LC-MS and/or TLCanalysis. The reaction mixture was concentrated to dryness thenre-dissolved in CH₂Cl₂ and washed with saturated NaHCO₃ solution. Theorganic extract was dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by silica gelchromatography (typical eluents included, for example, a mixture ofhexanes and EtOAc, or a mixture of CH₂Cl₂ and MeOH, or an 80:18:2mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desiredproduct iii-F. The product structures prepared according to GeneralProcedure F were confirmed by ¹H NMR and/or by mass analysis.

Example 7. General Procedure G

A mixture of the desired chlorotriazolopyrimidines i-G (1 equiv),desired aminomethyl heterocycle or benzylamine ii-G (1.2 equiv), andtriethylamine (NEt₃) (1.5-3.5 equiv) in 1,4-dioxane (˜0.2 M) was stirredat room temperature until the reaction was complete by LC-MS and/or TLCanalysis. The crude reaction mixture was directly purified by silica gelchromatography (typical eluents included either a mixture of hexanes andEtOAc or a mixture of CH₂Cl₂ and MeOH or an 80:18:2 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired product iii-G.The product structures prepared according to General Procedure G wereconfirmed by ¹H NMR and/or by mass analysis.

Example 8. General Procedure H

A mixture of the desired chloroimidazopyrimidines i-H (1 equiv), desiredaminomethyl heterocycle or benzylamine ii-H (1.2 equiv), andtriethylamine (NEt₃) (1.5-3.5 equiv) in 1,4-dioxane (˜0.1 M) was stirredat 70° C. until the reaction was complete by LC-MS and/or TLC analysis.The crude reaction mixture was directly purified by silica gelchromatography (typical eluents included, for example, a mixture ofhexanes and EtOAc, or a mixture of CH₂Cl₂ and MeOH, or an 80:18:2mixture of CH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desiredproduct iii-H. The product structures prepared according to GeneralProcedure H were confirmed by ¹H NMR and/or by mass analysis.

Example 9. General Procedure J

A mixture of the dichloroimidazopyrimidines i-J (1 equiv), desiredaminomethyl heterocycle i-J (1.2 equiv), and triethylamine (NEt₃)(1.5-3.5 equiv) in 1,4-dioxane (0.2 M) was stirred at 55° C. until thereaction was complete by LC-MS and/or TLC analysis.

The crude reaction mixture was directly purified by silica gelchromatography (typical eluents included either a mixture of hexanes andEtOAc or a mixture of CH₂Cl₂ and MeOH or a 90:9:1 mixture ofCH₂Cl₂/CH₃OH/concentrated NH₄OH) to afford the desired product iii-J.The product structures prepared according to General Procedure J wereconfirmed by ¹H NMR and/or by mass analysis.

Example 10.6-Chloro-N-(furan-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.53mmol), furfurylamine (0.051 mL, 0.58 mmol) and NEt₃ (0.11 mL, 0.79 mmol)in 1,4-dioxane (2 mL) was heated in a sealed tube at 150° C. for 30minutes then cooled to room temperature. The solvent was removed underreduced pressure and the residue was re-dissolved in CH₂Cl₂ and washedwith saturated NaHCO₃ solution, dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bysilica gel chromatography (20-100% EtOAc in hexanes) to afford the titlecompound as a light yellow solid (65 mg, 49%): ESI MS [M+H]⁺ 250; ¹H NMR(300 MHz, DMSO-d₆) δ 13.59 (s, 1H), 9.12 (t, J=4.8 Hz, 1H), 8.14 (s,1H), 7.63 (s, 1H), 6.44-6.38 (m, 2H), 4.84 (t, J=5.4 Hz, 2H).

Example 11.2-(6-Chloro-4-((furan-2-ylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol

A mixture of 2-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol(57 mg, 0.244 mmol), furfurylamine (32 mg, 0.329 mmol) and DIPEA (0.12mL, 0.687 mmol) in 1,4-dioxane (1.0 mL) was heated in a sealed tube at100° C. for 1.5 h, then cooled to room temperature. The mixture wasimmediately concentrated and the crude residue was purified bychromatography on silica gel (gradient 0-10% methanol in DCM) to affordthe title compound (67 mg, 93%) as an off-white solid: ESI MS [M+H]⁺294; ¹H NMR (300 MHz, DMSO-d₆) δ 9.17 (t, J=5.4 Hz, 1H), 8.15 (s, 1H),7.63 (s, 1H), 6.44-6.38 (m, 2H), 4.84 (t, J=5.7 Hz, 1H), 4.70 (d, J=5.5Hz, 2H), 4.26 (t, J=5.7 Hz, 2H), 3.77 (q, J=5.8 Hz, 2H).

Example 12.6-Chloro-1-(2-fluoroethyl)-N-(furan-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of 4,6-dichloro-1-(2-fluoroethyl)-1H-pyrazolo[3,4-d]pyrimidine(29.7 mg, 0.126 mmol), furfurylamine (36.3 mg, 0.374 mmol) and DIPEA(0.20 mL, 1.14 mmol) in 1,4-dioxane (2.4 mL) was heated in a sealed tubeat 150° C. for 1 h, then cooled to room temperature. The solvents wereremoved by rotary evaporation, and the crude residue was purified bychromatography on silica gel (gradient 0-100% EtOAc in hexanes). Theisolated chromatography product was then dissolved inacetonitrile/water, frozen and lyophilized to afford the title compound(18.2 mg, 48%) as an off-white solid: mp 125-128° C.; ESI MS [M+H]⁺ m/z296; ¹H NMR (300 MHz, DMSO-d₆) δ 9.22 (t, J=5.4 Hz, 1H), 8.20 (s, 1H),7.64 (dd, J=0.8, 1.8 Hz, 1H), 6.45-6.42 (m, 1H), 6.40-6.38 (m, 1H), 4.89(t, J=4.9 Hz, 1H), 4.75-4.68 (m, 3H), 4.59 (t, J=4.9 Hz, 1H), 4.50 (t,J=4.9 Hz, 1H).

Example 13.2-(6-Chloro-4-((pyridin-4-ylmethyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol

A mixture of 2-(4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethanol(30 mg, 0.129 mmol), 4-(aminomethyl)pyridine (18.5 mg, 0.171 mmol) andDIPEA (0.12 mL, 0.687 mmol) in 1,4-dioxane (1.2 mL) was heated in asealed tube at 100° C. for 45 min, then cooled to room temperature. Thesolvents were removed by rotary evaporation, and the crude residue waspurified by chromatography on silica gel (gradient 0-100% CMA indichloromethane). The product isolated from chromatography was dissolvedin acetonitrile/water, frozen and lyophilized to afford the titlecompound (27.1 mg, 69%) as a light tan solid: ESI MS [M+H]⁺ m/z 305; ¹HNMR (300 MHz, DMSO-d₆) δ 9.29 (t, J=5.8 Hz, 1H), 8.52 (dd, J=1.6, 4.4Hz, 2H), 8.18 (s, 1H), 7.34 (d, J=5.9 Hz, 2H), 4.84 (t, J=5.7 Hz, 1H),4.74 (d, J=5.9 Hz, 2H), 4.28 (t, J=5.8 Hz, 2H), 3.78 (q, J=5.8 Hz, 2H).

Example 14.6-Chloro-N-(pyridin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (83 mg, 0.439mmol), 4-(aminomethyl)pyridine (67 mg, 0.619 mmol) and DIPEA (0.30 mL,1.72 mmol) in 1,4-dioxane (2.0 mL) was heated in a sealed tube at 100°C. for 45 min, then cooled to room temperature. The solvents wereremoved by rotary evaporation, and the crude residue was purified bychromatography on silica gel (gradient 0-100% CMA in dichloromethane).The product isolated from chromatography was dissolved inacetonitrile/water, frozen and lyophilized to afford the title compound(43.8 mg, 38%) as an off-white solid: ESI MS [M+H]⁺ m/z 261; ¹H NMR (300MHz, DMSO-d₆) δ 13.63 (br s, 1H), 9.25 (t, J=6.3 Hz, 1H), 8.53 (d, J=5.9Hz, 2H), 8.17 (s, 1H), 7.35 (d, J=5.8 Hz, 2H), 4.73 (d, J=5.7 Hz, 2H).

Example 15.6-Chloro-N-(pyrimidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (29 mg, 0.153mmol), 4-(aminomethyl)pyrimidine hydrochloride (31.8 mg, 0.218 mmol) andDIPEA (0.14 mL, 0.802 mmol) in 1,4-dioxane (1.0 mL) was heated in asealed tube at 100° C. for 90 min, then cooled to room temperature. Thesolvents were removed by rotary evaporation, and the crude residue waspurified by chromatography on silica gel (gradient 0-10% MeOH indichloromethane). The product isolated from chromatography was dissolvedin acetonitrile/water, frozen and lyophilized to afford the titlecompound (35.3 mg, 88%) as an off-white solid: ESI MS [M+H]⁺ m/z 262; ¹HNMR (500 MHz, DMSO-d₆) δ 13.64 (br s, 1H), 9.34 (t, J=5.9 Hz, 1H), 9.14(d, J=1.3 Hz, 1H), 8.74 (d, J=5.2 Hz, 1H), 8.20 (s, 1H), 7.48 (d, J=4.3Hz, 1H), 4.79 (d, J=5.9 Hz, 2H).

Example 16.6-Chloro-N-(thiazol-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine

A mixture of 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine (53.6 mg, 0.284mmol), 2-(aminomethyl)thiazole dihydrochloride (75.4 mg, 0.403 mmol) andDIPEA (0.30 mL, 1.72 mmol) in 1,4-dioxane (1.2 mL) was heated in asealed tube at 125° C. for 3 h, then cooled to room temperature. Thesolvents were removed by rotary evaporation, and the crude residue waspurified by chromatography on silica gel (gradient 0-10% MeOH indichloromethane). The product isolated from chromatography was dissolvedin acetonitrile/water, frozen and lyophilized, then dried under vacuumat 75° C. for 16 h to afford the title compound (45.5 mg, 60%) as anoff-white solid: ESI MS [M+H]⁺ m/z 267; ¹H NMR (300 MHz, DMSO-d₆) δ13.63 (br s, 1H), 9.52 (t, J=5.9 Hz, 1H), 8.17 (s, 1H), 7.77 (d, J=3.2Hz, 1H), 7.66 (d, J 3.3 Hz, 1H), 4.98 (d, J=6.0 Hz, 2H).

Example 17.5-(methylthio)-N-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine

Step 1. 5-(methylthio)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yltrifluoromethanesulfonate

A solution of5-(methylthio)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7(6H)-one (79 mg,0.431 mmol) in pyridine (1.0 mL) at 0° C. was treated withtrifluoromethanesulfonic anhydride (0.08 mL, 0.48 mmol) and was allowedto warm to room temperature while stirring for 16 h. All volatiles wereremoved by rotary evaporation, and the crude residue (130 mg) was usedimmediately in the following step.

Step 2.5-(methylthio)-N-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-amine

A mixture of crude5-(methylthio)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-7-yltrifluoromethanesulfonate (130 mg, 0.43 mmol), 2-(aminomethyl)thiazoledihydrochloride (99 mg, 0.529 mmol) and DIPEA (0.33 mL, 1.89 mmol) in1,4-dioxane (2.0 mL) was stirred at room temperature 16.5 h. Allvolatiles were removed by rotary evaporation, and the crude residue waspurified by chromatography on silica gel (gradient 0-20% methanol inDCM) to afford the title compound (22 mg, 18% over 2 steps) as anoff-white solid: ESI MS m/z 280 [M+H]⁺; ¹H NMR (500 MHz, DMSO-d₆) δ 9.99(t, J=6.0 Hz, 1H), 8.45 (s, 1H), 7.76 (d, J=3.3 Hz, 1H), 7.67 (d, J=3.3Hz, 1H), 4.97 (d, J=6.1 Hz, 2H), 2.50 (s, 3H).

Example 18.2-chloro-4-((pyridin-4-ylmethyl)amino)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one

A mixture of 2,4-dichloro-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (29.5 mg,0.145 mmol), 4-(aminomethyl)pyridine (18.6 mg, 0.172 mmol) and DIPEA(0.04 mL, 0.23 mmol) in 1,4-dioxane (1.2 mL) was heated in a sealed tubeat 60° C. for 6.5 h, then cooled to room temperature. The mixture wasimmediately concentrated and the crude residue was purified bychromatography on silica gel (gradient 0-100% CMA in dichloromethane).The isolated product was dissolved in acetonitrile/water, frozen andlyophilized to afford the title compound (5.0 mg, 93%) as an off-whitesolid: ESI MS [M+H]⁺ m/z 276; ¹H NMR (300 MHz, DMSO-d₆) δ 11.30 (br s,1H), 8.48 (dd, J=1.6, 4.4 Hz, 2H), 8.09 (br s, 1H), 7.26 (d, J=5.7 Hz,2H), 4.47 (d, J=6.2 Hz, 2H), 3.41 (s, 2H).

Example 19. 2-Chloro-7-methyl-N-(thiazol-2-ylmethyl)-7H-purin-6-amine

A mixture of 2,6-dichloro-7-methyl-7H-purine (60 mg, 0.30 mmol),thiazol-2-ylmethanamine dihydrochloride (67 mg, 0.36 mmol) andtriethylamine (0.15 mL, 1.05 mmol) in 1,4-dioxane (2 mL) was stirred at75° C. overnight. After this time the mixture was concentrated and theresidue purified by column chromatography (silica gel, 0-6% MeOH inCH₂Cl₂) to afford the title compound as a white solid (48 mg, 58%): ESIMS (M+H) m/z 281; ¹H NMR (300 MHz, DMSO-d₆) δ 8.27 (br s, 2H), 7.75 (d,J=3.3 Hz, 1H), 7.63 (d, J=3.3 Hz, 1H), 4.95 (d, J=5.7 Hz, 2H), 4.03 (s,3H).

Example 20. 2-Chloro-N-(furan-2-ylmethyl)-7-methyl-7H-purin-6-amine

A mixture of 2,6-dichloro-7-methyl-7H-purine (60 mg, 0.30 mmol),furfurylamine (0.028 mL, 0.31 mmol) and triethylamine (0.043 mL, 0.59mmol) in 1,4-dioxane (5 mL) was stirred at 50° C. overnight. After thistime the mixture was concentrated and the residue purified by columnchromatography (silica gel, 0-6% MeOH in CH₂Cl₂) to afford the titlecompound as an off-white solid (69 mg, 88%): ESI MS (M+H) m/z 264; ¹HNMR (500 MHz, DMSO-d₆) δ 8.21 (s, 1H), 7.84 (s, 1H), 7.58 (s, 1H),6.41-6.34 (m, 2H), 4.66 (d, J=5.5 Hz, 2H), 4.01 (s, 3H).

Example 21. 2-Chloro-7-methyl-N-(pyridin-4-ylmethyl)-7H-purin-6-amine

A mixture of 2,6-dichloro-7-methyl-7H-purine (60 mg, 0.30 mmol),4-(aminomethyl)pyridine (0.031 mL, 0.31 mmol) and triethylamine (0.0.43mL, 0.59 mmol) in 1,4-dioxane (5 mL) was stirred at 50° C. overnight.After this time the mixture was concentrated and the residue purified bycolumn chromatography (silica gel, 0-6% MeOH, CH₂Cl₂) to afford thetitle compound as an off-white solid (43 mg, 53%): ESI MS (M+H) m/z 275;¹H NMR (500 MHz, DMSO-d₆) δ 8.49 (d, J=6.0 Hz, 2H), 8.24 (s, 1H), 7.97(br s, 1H), 7.38 (d, J=6.0 Hz, 2H), 4.70 (t, J=6.0 Hz, 2H), 4.07 (s,3H).

Example 22. 2-Chloro-7-methyl-N-(pyrimidin-4-ylmethyl)-7H-purin-6-amine

A mixture of 2,6-dichloro-7-methyl-7H-purine (60 mg, 0.30 mmol),4-(aminomethyl)pyrimidine hydrochloride (45 mg, 0.31 mmol) andtriethylamine (0.043 mL, 0.59 mmol) in 1,4-dioxane (5 mL) was stirred at50° C. overnight. After this time the mixture was concentrated and theresidue purified by column chromatography (silica gel, 0-6% MeOH,CH₂Cl₂) to afford the title compound as a tan solid (57 mg, 70%): ESI MS(M+H) m/z 276; ¹H NMR (500 MHz, DMSO-d₆) δ 9.12 (d, J=1.0 Hz, 1H), 8.71(d, J=5.5 Hz, 2H), 8.27 (s, 1H), 8.01 (s, 1H), 7.54 (d, J=5.5 Hz, 1H),4.75 (d, J=6.0 Hz, 2H), 4.09 (s, 3H).

Example 23.2-Chloro-7-methyl-8-propoxy-N-(pyridin-4-ylmethyl)-7H-purin-6-amine

A mixture of 2,6-dichloro-7-methyl-8-propoxy-7H-purine (40 mg, 0.15mmol), 4-(aminomethyl)pyridine (60 mg, 0.54 mmol) and triethylamine(0.04 mL, 0.29 mmol) in 1,4-dioxane was stirred at 90° C. for 8 h. Afterthis time the mixture was concentrated and the residue purified bycolumn chromatography (silica, 0-5% MeOH in CH₂Cl₂) to provide2-chloro-7-methyl-8-propoxy-N-(pyridin-4-ylmethyl)-7H-purin-6-amine (9mg, 18%): ESI MS (M+H) 333; ¹H NMR (500 MHz, DMSO-d₆) δ 8.49-8.48 (m,2H), 7.66 (t, J=5.7 Hz, 1H), 7.36-7.34 (m, 2H), 4.65 (d, J=5.7 Hz, 2H),4.44 (t, J=6.5 Hz, 2H), 3.76 (s, 3H), 1.84-1.76 (m, 2H), 0.99 (t, J=7.4Hz, 3H).

Example 24.2-Chloro-7-methyl-8-propoxy-N-(thiazol-2-ylmethyl)-7H-purin-6-amine

A mixture of 2,6-dichloro-7-methyl-8-propoxy-7H-purine (28 mg, 0.11mmol), thiazol-2-ylmethanamine dihydrochloride (70 mg, 0.37 mmol) andtriethylamine (0.16 mL, 1.14 mmol) in DMSO (1.5 mL) was stirred at 60°C. for 2 h. After this time the mixture was cooled to room temperature,diluted with EtOAc and washed with water and brine. The organic layerwas concentrated and the resulting residue was purified by columnchromatography (silica, 0-5% MeOH in CH₂Cl₂) to provide2-chloro-7-methyl-8-propoxy-N-(thiazol-2-ylmethyl)-7H-purin-6-amine (21mg, 56%): ESI MS (M+H) 339; ¹H NMR (500 MHz, DMSO-d₆) δ 7.93 (s, 1H),7.73 (d, J=3.3 Hz, 1H), 7.61 (d, J=3.3 Hz, 1H), 4.90 (s, 2H), 4.44 (t,J=6.5 Hz, 2H), 3.73 (s, 3H), 1.84-1.76 (m, 2H), 0.99 (t, J=7.4 Hz, 3H).

Example 25.2-Chloro-7-methyl-8-propoxy-N-(pyrimidin-4-ylmethyl)-7H-purin-6-amine

A mixture of 2,6-dichloro-7-methyl-8-propoxy-7H-purine (36 mg, 0.14mmol), 4-(aminomethyl)pyrimidine hydrochloride (70 mg, 0.48 mmol) andtriethylamine (0.20 mL, 1.43 mmol) in DMSO (1.5 mL) was stirred at 50°C. for 7 h. After this time the mixture was cooled to room temperature,diluted with EtOAc and washed with water and brine. The organic layerwas concentrated and the resulting residue was purified by columnchromatography (silica, 0-7% MeOH in CH₂Cl₂) to provide2-chloro-7-methyl-8-propoxy-N-(pyrimidin-4-ylmethyl)-7H-purin-6-amine(24 mg, 51%): ESI MS (M+H) 334; ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (d,J=1.3 Hz, 1H), 8.71 (d, J=5.2 Hz, 1H), 7.70 (t, J=5.8 Hz, 1H), 7.50 (dd,J=5.2, 1.3 Hz, 1H), 4.70 (d, J=5.8 Hz, 2H), 4.45 (t, J=6.5 Hz, 2H), 3.31(s, 3H), 1.85-1.77 (m, 2H), 1.00 (t, J=7.4 Hz, 3H).

Example 26.5-Chloro-N-(furan-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine

Following general procedure F, 5,7-Dichlorothiazolo[5,4-d]pyrimidine andfurfurylamine were converted to5-chloro-N-(furan-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine as a whitesolid (35 mg, 60%): ESI MS (M+H)⁺ m/z 267; ¹H NMR (300 MHz, DMSO-d₆) δ9.27-9.21 (m, 2H), 7.58 (dd, J=1.8, 0.9 Hz, 1H), 6.40 (dd, J=3.0, 1.8Hz, 1H), 6.31 (d, J=2.4 Hz, 1H), 4.66 (d, J=6.0 Hz, 2H).

Example 27.5-Chloro-N-(pyridin-4-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine

Following general procedure F, 5,7-Dichlorothiazolo[5,4-d]pyrimidine and4-(aminomethyl)pyridine were converted to5-chloro-N-(pyridin-4-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine as awhite solid (55 mg, 83%): ESI MS (M+H)⁺ m/z 278; ¹H NMR (300 MHz,DMSO-d₆) δ 9.38 (t, J=6.3 Hz, 1H), 9.31 (s, 1H), 8.50 (d, J=6.0 Hz, 2H),7.33 (d, J=6.0 Hz, 2H), 4.70 (d, J=6.3 Hz, 2H).

Example 28.5-Chloro-2-(cyclobutylmethoxy)-N-(thiazol-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine

Step 1.2-Bromo-5-chloro-N-(thiazol-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine

A mixture of 2-bromo-5,7-dichlorothiazolo[5,4-d]pyrimidine (50 mg, 0.18mmol), thiazol-2-ylmethanamine dihydrochloride (100 mg, 0.53 mmol) andtriethylamine (0.23 mL, 1.65 mmol) in DMSO (3 mL) was stirred at 50° C.for 2 h. After this time the mixture was cooled to room temperature,diluted with EtOAc and washed with water and brine. The organic layerwas dried over sodium sulfate, filtered and concentrated to obtain2-bromo-5-chloro-N-(thiazol-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine(69 mg), which was used in the next step without further purification:ESI MS (M+H) 362; ¹H NMR (500 MHz, DMSO-d₆) δ 9.65 (t, J=5.8 Hz, 1H),7.75 (d, J=3.2 Hz, 1H), 7.64 (d, J=3.2 Hz, 1H), 4.93 (d, J=6.0 Hz, 2H).

Step 2.5-Chloro-2-(cyclobutylmethoxy)-N-(thiazol-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine

Sodium hydride (60% in mineral oil, 8 mg, 0.20 mmol) was carefully addedto cyclobutylmethanol (1.0 mL) followed by2-bromo-5-chloro-N-(thiazol-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine(69 mg, 0.19 mmol). The resulting mixture was stirred at 70° C. for 20min. After this time the mixture was diluted with EtOAc and washed withwater and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated. The residue was purified by columnchromatography (silica, 0-4% MeOH, CH₂Cl₂) to provide5-chloro-2-(cyclobutylmethoxy)-N-(thiazol-2-ylmethyl)thiazolo[5,4-d]pyrimidin-7-amine(8 mg, 12% over two steps): ESI MS (M+H)⁺ 368; ¹H NMR (500 MHz, DMSO-d₆)δ 8.89 (d, J=5.8 Hz, 1H), 7.74 (d, J=3.3 Hz, 1H), 7.62 (d, J=3.3 Hz,1H), 4.90 (d, J=5.8 Hz, 2H), 4.57 (d, J=6.8 Hz, 2H), 2.86-2.80 (m, 1H),2.11-2.06 (m, 2H), 1.96-1.81 (m, 4H).

Example 29.N⁷-(furan-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7-diamine

To a solution of 7-chloro-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine (31mg, 0.18 mmol) in 1,4-dioxane (2 mL) was added furfurylamine (0.024 mL,0.27 mmol) followed by triethylamine (0.075 mL, 0.54 mmol). The reactionwas heated at 80° C. for 30 minutes then cooled to room temperature. Thereaction mixture was partitioned between dichloromethane and saturatedNaHCO₃ solution and the organic layer was collected and dried oversodium sulfate. The crude material was purified by silica gelchromatography (CH₂Cl₂ to 3% MeOH in CH₂Cl₂) to afford the titlecompound as an-off white solid (30 mg, 73%): ESI MS (M+H)⁺ m/z 232; ¹HNMR (500 MHz, DMSO-d₆) δ 14.50 (bs s, 1H), 7.91 (br s, 1H), 7.47 (dd,J=1.5, 0.5 Hz, 1H), 6.34 (dd, J=3.0, 1.5 Hz, 1H), 6.29 (dd, J=3.0, 1.0Hz, 1H), 5.87 (br s, 2H), 4.78 (s, 2H).

Example 30.5-Chloro-N-(furan-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-amine

To a solution of LiCL (23 mg, 0.55 mmol) in N,N-dimethylacetamide (DMA,1 mL) at 0° C. was addedN⁷-(furan-2-ylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7-diamine(32 mg, 0.14 mmol), isoamyl nitrite (0.045 mL, 0.22 mmol), followed bythionyl chloride (0.013 mL, 0.17 mmol). The reaction was stirredovernight at room temperature. After this time, the reaction mixture wasdiluted with EtOAc and washed with water (3×15 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The crude material waspurified by silica gel chromatography (CH₂Cl₂ to 4% MeOH in CH₂Cl₂) toafford the title compound as a white solid (8 mg, 23%): ESI MS (M−H)⁻m/z 249; ¹H NMR (500 MHz, DMSO-d₆) δ 16.11 (br s, 1H), 9.07 (br s, 1H),7.50-7.46 (m, 1H), 6.36-6.28 (m, 2H), 4.80 (br s, 2H).

Example 31.5-Chloro-N-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

Following general procedure G,5,7-Dichloro-[1,2,4]triazolo[1,5-a]pyrimidine and2-(aminomethyl)thiazole dihydrochloride were converted to5-chloro-N-(thiazol-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amineas a white solid (53 mg, 80%). ESI MS (M+H) m/z 267; ¹H NMR (300 MHz,DMSO-d₆) δ 9.48 (s, 1H), 8.56 (s, 1H), 7.80 (d, J=3.3 Hz, 1H), 7.10 (d,J=3.3 Hz, 1H), 6.69 (s, 1H), 5.01 (s, 2H).

Example 32.5-Chloro-N-(furan-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

Following general procedure G,5,7-Dichloro-[1,2,4]triazolo[1,5-a]pyrimidine and furfurylamine wereconverted to5-chloro-N-(furan-2-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine asa light yellow solid (20 mg, 51%). ESI MS (M+H) m/z 250; ¹H NMR (300MHz, DMSO-d₆) δ 9.25 (br s, 1H), 8.51 (s, 1H), 7.63 (dd, J=1.8, 0.9 Hz,1H), 6.68 (s, 1H), 6.47 (d, J=2.4 Hz, 1H), 6.42 (dd, J=3.3, 1.8 Hz, 1H),4.66 (d, J=5.1 Hz, 2H).

Example 33.5-Chloro-N-(pyridin-4-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

Following general procedure G,5,7-Dichloro-[1,2,4]triazolo[1,5-a]pyrimidine and4-(aminomethyl)pyridine were converted to5-chloro-N-(pyridin-4-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amineas a light yellow solid (50 mg, 87%). ESI MS (M+H) m/z 261; ¹H NMR (300MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.55-8.51 (m, 3H), 7.38 (d, J=6.0 Hz, 2H),6.53 (s, 1H), 4.72 (s, 2H).

Example 34.5-Chloro-N-(pyrimidin-4-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine

Following general procedure G,5,7-Dichloro-[1,2,4]triazolo[1,5-a]pyrimidine and4-(aminomethyl)pyrimidine hydrochloride were converted to5-chloro-N-(pyrimidin-4-ylmethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-amineas an off-white solid (41 mg, 75%). ESI MS (M+H) m/z 262; ¹H NMR (300MHz, DMSO-d₆) δ 9.22 (br s, 1H), 9.14 (d, J=1.2 Hz, 1H), 8.76 (d, J=5.4Hz, 1H), 8.56 (s, 1H), 7.53 (dd, J=5.4, 1.5 Hz, 1H), 6.60 (s, 1H), 4.81(d, J=5.1 Hz, 2H).

Example 35.7-Chloro-N-(thiazol-2-ylmethyl)imidazo[1,2-a]pyrimidin-5-amine

Following general procedure H, 5,7-Dichloroimidazo[1,2-a]pyrimidine and2-(aminomethyl)thiazole dihydrochloride were converted to7-chloro-N-(thiazol-2-ylmethyl)imidazo[1,2-a]pyrimidin-5-amine as alight yellow solid (22 mg, 40%). ESI MS (M+H) m/z 266; ¹H NMR (300 MHz,DMSO-d₆) δ 9.02 (s, 1H), 7.96 (d, J=1.5 Hz, 1H), 7.81 (d, J=3.3 Hz, 1H),7.72 (d, J=3.3 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 6.34 (s, 1H), 5.02 (s,2H).

Example 36. 7-Chloro-N-(furan-2-ylmethyl)imidazo[1,2-a]pyrimidin-5-amine

Following general procedure H, 5,7-Dichloroimidazo[1,2-a]pyrimidine andfurfurylamine were converted to7-chloro-N-(furan-2-ylmethyl)imidazo[1,2-a]pyrimidin-5-amine as a whitesolid (20 mg, 40%). ESI MS (M+H) m/z 249; ¹H NMR (500 MHz, DMSO-d₆) δ8.65 (br s, 1H), 7.95 (s, 1H), 7.64 (dd, J=2.0, 1.0 Hz, 1H), 7.53 (d,J=2.0 Hz, 1H), 6.51-6.44 (m, 2H), 6.34 (s, 1H), 4.65 (s, 2H).

Example 38.7-chloro-N-(pyrimidin-4-ylmethyl)imidazo[1,2-a]pyrimidin-5-amine

Following general procedure H, 5,7-Dichloroimidazo[1,2-a]pyrimidine and4-(aminomethyl)pyrimidine hydrochloride were converted to7-chloro-N-(pyrimidin-4-ylmethyl)imidazo[1,2-a]pyrimidin-5-amine as anoff-white solid (22 mg, 42%). ESI MS (M+H) m/z 261; ¹H NMR (300 MHz,DMSO-d₆) δ 9.14 (d, J=1.5 Hz, 1H), 8.84 (t, J=6.3 Hz, 1H), 7.78 (d,J=5.1 Hz, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.58-7.56 (m, 2H), 6.18 (s, 1H),4.80 (d, J=6.0 Hz, 2H).

Example 39.5-chloro-N-(thiazol-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine

Following general procedure H, 5,7-Dichloropyrazolo[1,5-a]pyrimidine and2-(aminomethyl)thiazole dihydrochloride were converted to5-chloro-N-(thiazol-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine as anoff-white solid (82 mg, 88%). ESI MS (M+H) m/z 266; ¹H NMR (300 MHz,DMSO-d₆) δ 9.14 (br s, 1H), 8.19 (d, J=2.4 Hz, 1H), 7.79 (d, J=3.3 Hz,1H), 7.69 (d, J=3.3 Hz, 1H), 6.47 (d, J=2.1 Hz, 1H), 6.32 (s, 1H), 4.98(br s, 2H).

Example 40.5-Chloro-N-(furan-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine

Following general procedure H, 5,7-Dichloropyrazolo[1,5-a]pyrimidine aand furfurylamine were converted to5-chloro-N-(furan-2-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine as a lightyellow solid (62 mg, 70%). ESI MS (M+H) m/z 249; ¹H NMR (500 MHz,DMSO-d₆) δ 8.65 (br s, 1H), 8.14 (d, J=2.4 Hz, 1H), 7.62 (dd, J=1.8, 0.9Hz, 1H), 6.45-6.41 (m, 3H), 6.35 (s, 1H), 4.64 (br s, 2H).

Example 41.5-chloro-N-(pyrimidin-4-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine

Following general procedure H, 5,7-Dichloropyrazolo[1,5-a]pyrimidine aand 4-(aminomethyl)pyrimidine hydrochloride were converted to5-chloro-N-(pyrimidin-4-ylmethyl)pyrazolo[1,5-a]pyrimidin-7-amine as awhite solid (69 mg, 77%). ESI MS (M+H) m/z 261; ¹H NMR (300 MHz,DMSO-d₆) δ 9.15 (d, J=1.2 Hz, 1H), 8.90 (br s, 1H), 8.76 (d, J=5.1 Hz,1H), 8.19 (d, J=2.4 Hz, 1H), 7.49 (dd, J=5.4, 1.5 Hz, 1H), 6.47 (d,J=2.4 Hz, 1H), 6.23 (s, 1H), 4.79 (d, J=5.4 Hz, 2H).

Example 42. 2-Chloro-N-(furan-2-ylmethyl)thieno[2,3-d]pyrimidin-4-amine

To a solution of 2,4-dichlorothieno[2,3-d]pyrimidine (142 mg, 0.69 mmol)in 1,4-dioxane (10 mL) was added furfurylamine (0.07 mL, 0.76 mmol)followed by triethylamine (0.14 mL, 1.03 mmol). The reaction was heatedat 100° C. for 4 h then cooled to room temperature. The reaction mixturewas partitioned between dichloromethane and saturated NaHCO₃ solutionand the organic layer was collected and dried over sodium sulfate. Thecrude material was purified by silica gel chromatography (5-50% EtOAc inhexanes) to afford the title compound as a white solid (158 mg, 86%):ESI MS (M+H)⁺ m/z 266; ¹H NMR (300 MHz, DMSO-d₆) δ 8.91 (t, J=5.4 Hz,1H), 7.65-7.60 (m, 3H), 6.43 (dd, J=3.3, 1.8 Hz, 1H), 6.37 (d, J=2.7 Hz,1H), 4.69 (d, J=5.4 Hz, 2H).

Example 43.2-Chloro-N-(furan-2-ylmethyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine(188 mg, 0.99 mmol) in 1,4-dioxane (10 mL) was added furfurylamine(0.096 mL, 1.09 mmol) followed by triethylamine (0.14 mL, 1.48 mmol).The reaction was heated at 100° C. for 2 h then cooled to roomtemperature. The reaction mixture was partitioned betweendichloromethane and saturated NaHCO₃ solution and the organic layer wascollected and dried over sodium sulfate. The crude material was purifiedby silica gel chromatography (5-50% EtOAc in hexanes) to afford thetitle compound as a white solid (135 mg, 55%): ESI MS (M+H)⁺ m/z 250; ¹HNMR (300 MHz, DMSO-d₆) δ 7.85 (t, J=5.7 Hz, 1H), 7.58 (dd, J=1.8, 0.6Hz, 1H), 6.39 (dd, J=3.3, 1.8 Hz, 1H), 6.27 (dd, J=3.3, 0.6 Hz, 1H),4.52 (d, J=5.7 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.62 (t, J=7.5 Hz, 2H),2.05-1.95 (m, 2H).

Table 2 shows a list of representative compounds that were preparedusing the methods described herein and characterized via massspectrometry.

TABLE 2 Cpd No. m/z Cpd No. m/z Cpd No. m/z  (1) 240 (143) 341 (303) 308 (2) 317 (144) 302 (305) 333  (3) 215 (145) 272 (306) 352  (4) 308 (146)265 (307) 345  (4) 216 (147) 305 (308) 334  (5) 308 (148) 291 (309) 322 (7) 227 (149) 258 (310) 327  (8) 231 (150) 295 (311) 322  (9) 270 (151)285 (312) 369  (10) 294 (152) 284 (315) 321  (11) 258 (153) 334 (317)321  (12) 244 (154) 307 (318) 339  (13) 280 (155) 321 (319) 336  (14)240 (156) 289 (320) 306  (15) 284 (157) 310 (321) 332  (16) 233 (158)293 (323) 251  (17) 284 (159) 281 (324) 351  (18) 284 (160) 345 (326)346  (19) 245 (161) 320 (327) 432  (20) 230 (162) 275 (328) 341  (21)232 (163) 299 (329) 380  (22) 215 (165) 292 (331) 360  (23) 294 (166)293 (332) 365  (24) 284 (167) 307 (333) 321  (25) 254 (168) 346 (334)359  (26) 308 (169) 254 (338) 348  (27) 241 (170) 279 (339) 363  (28)258 (171) 272 (340) 375  (29) 254 (172) 306 (343) 249  (30) 241 (173)332 (344) 367  (31) 242 (174) 261 (346) 353  (32) 254 (175) 251 (347)347  (33) 284 (176) 261 (348) 380  (34) 230 (177) 292 (349) 342  (35)251 (178) 250 (350) 260  (36) 246 (179) 262 (351) 311  (37) 226 (180)306 (352) 278  (38) 292 (181) 292 (353) 261  (39) 294 (182) 333 (354)277  (40) 270 (183) 332 (355) 260  (41) 241 (184) 291 (356) 261  (42)251 (185) 311 (357) 261  (43) 233 (186) 307 (358) 262  (44) 284 (187)306 (359) 274  (45) 230 (188) 275 (360) 262  (46) 230 (188) 292 (361)261  (47) 241 (189) 274 (362) 387  (48) 215 (190) 346 (363) 280  (49)242 (191) 307 (364) 280  (50) 218 (192) 312 (365) 276  (51) 229 (193)306 (366) 275  (52) 232 (194) 306 (367) 251  (53) 262 (195) 320 (368)281  (54) 230 (197) 374 (369) 274  (55) 249 (198) 249 (370) 311  (57)249 (199) 291 (371) 245  (58) 234 (200) 414 (372) 266  (59) 282 (201)292 (373) 266  (60) 259 (202) 323 (374) 292  (61) 266 (203) 334 (375)297  (62) 244 (204) 293 (376) 297  (63) 228 (205) 283 (377) 283  (64)228 (206) 320 (378) 267  (65) 256 (207) 294 (379) 250  (66) 215 (208)300 (380) 244  (67) 258 (210) 295 (381) 267  (68) 228 (211) 327 (382)341  (69) 232 (212) 329 (383) 276  (70) 284 (213) 306 (384) 330  (71)307 (215) 316 (385) 288  (72) 341 (216) 302 (386) 341  (73) 294 (219)321 (387) 370  (74) 259 (221) 336 (388) 361  (75) 307 (223) 272 (389)325  (76) 341 (224) 280 (390) 344  (77) 293 (225) 323 (391) 379  (78)307 (226) 278 (392) 365  (79) 341 (227) 279 (393) 369  (80) 260 (228)294 (394) 396  (81) 267 (229) 295 (395) 347  (82) 229 (230) 297 (396)377  (83) 291 (231) 304 (397) 366  (84) 263 (232) 308 (398) 362  (86)325 (233) 294 (399) 379  (87) 230 (234) 315 (400) 530  (88) 327 (235)293 (401) 403  (89) 326 (236) 316 (402) 394  (90) 264 (237) 290 (403)230  (91) 306 (238) 293 (404) 227  (92) 292 (239) 308 (405) 284  (93)326 (240) 321 (406) 217  (94) 307 (241) 291 (407) 230  (95) 290 (241)281 (408) 217  (96 256 (242) 304 (409) 228  (97) 292 (243) 293 (410) 217 (98) 307 (244) 290 (411) 230  (99) 341 (245) 296 (465) 216 (100) 260(246) 331 (467) 240 (101) 289 (247) 291 (469) 378 (102) 335 (248) 276(470) 297 (103) 275 (249) 324 (471) 450 (104) 321 (250) 318 (472) 350(105) 307 (251) 260 (473) 367 (106) 303 (252) 307 (474) 378 (107) 266(254) 293 (475) 367 (108) 307 (255) 277 (476) 395 (109) 279 (258) 319(477) 322 (110) 261 (259) 320 (478) 336 (111) 311 (260) 309 (479) 335(112) 279 (261) 292 (480) 350 (113) 279 (262) 307 (481) 386 (114) 278(263) 274 (482) 383 (115) 263 (264) 342 (483) 373 (116) 284 (265) 339(484) 332 (117) 321 (266) 294 (485) 349 (118) 293 (267) 334 (486) 318(119) 274 (268) 275 (487) 278 (120) 274 (269) 322 (488) 387 (121) 318(270) 348 (489) 334 (122) 304 (271) 325 (490) 356 (123) 280 (272) 333(491) 339 (124) 280 (273) 305 (492) 370 (125) 324 (274) 325 (493) 353(126) 275 (275) 310 (494) 278 (127) 305 (276) 341 (495) 278 (128) 319(277) 319 (496) 361 (129) 262 (278) 341 (497) 339 (130) 326 (280) 295(498) 267 (131) 267 (282) 319 (499) 379 (132) 331 (287) 335 (500) 374(133) 291 (289) 337 (501) 267 (134) 261 (290) 335 (502) 269 (135) 322(291) 349 (503) 252 (136) 300 (292) 308 (504) 355 (136) 275 (293) 324(505) 364 (137) 308 (294) 331 (506) 374 (138) 323 (296) 338 (507) 374(139) 331 (297) 324 (508) 351 (140) 293 (299) 359 (509) 368 (141) 301(300) 336 (510) 310 (142) 307 (302) 365 (511) 341

Example 44. Primary Splicing Assay

The primary splicing assay was carried out using human embryonic kidney293T (HEK293T) routinely maintained in Dulbecco's Modified Eagle's media(DMEM) (GIBCO ref 11995-065). The media was supplemented with 2 mML-glutamine, 1% penicillin/streptomycin and 10% fetal bovine serum(SIGMA cat. 12306C). Splicing analysis was made possible by using an FD(familial dysautomonia) IKBKAP minigene which contained exon 19 throughexon 21, including intervening introns, and also the T->C Thymine tocytosine transition located 6 base-pairs from the end of IKBKAP exon 20;See SEQ ID NO:3 for the complete sequence of plasmid pcDNA3.1/V5HisTOPOwith Renilla-Familial Dysautonomia minigene-Firefly. Firefly luciferase(SEQ ID NO:14) was utilized as a splicing reporter, located downstreamof exon 21, and Renilla luciferase (SEQ ID NO:13) was used as a control,located upstream of exon 19. The sequence of exon 19 is presented as SEQID NO:7; the Intron between Exon 19 and Exon 20 is SEQ ID NO:8; exon 20is SEQ ID NO:9; the intron between Exon 19 and Exon 20 is SEQ ID NO:10;exon 21 is SEQ ID NO:11, and the spliced sequence of exons 19-20-21 isSEQ ID NO:12. HEK293T cells were plated in a 6-well plate 24 hours priorto transfection. Transfection was carried out using a mixture ofOpti-MEM (GIBCO ref. 31985), IKBKAP minigene, and Fugene HD (PROMEGAref. E2311), incubated in DMEM media containing HEK293T cells at 37° C.The ratio of Opti-MEM, minigene, and Fugene was kept at approximately9:1.5:1, with a total volume of 150 μL of transfection mixture appliedper well.

After 4 hours of transfection, the cells were then plated in a 96-wellplate coated with poly-L-lysine (SIGMA cat. P4707) for treatmentscheduled 24 hours later. Treatment with compounds was performed at 8concentrations, each diluted in PBS with a final DMSO concentration of0.5%. After 24 hours of treatment, cells were washed in thepoly-L-lysine coated 96-well plate using PBS and subsequently harvestedusing Passive Lysis Buffer (Promega cat. E196). Cell lysate wastransferred to a black and white 96-well plate and analyzed for splicingcorrection using a Glomax luminometer (PROMEGA GloMax® 96 MicroplateLuminometer w/Dual Injectors cat. E6521) and Promega Dual Glo Fireflyand Stop and Glo Renilla reagents (Cat. E196). The compound's ability tocorrect splicing and promote exon 20 inclusion was marked by an increasein Firefly signal. Renilla signal, which is independent of exon 20inclusion, was used to correct for cell number. Using the ratio ofFirefly to Renilla signal, a dose response curve was produced, whichreferenced kinetin and DMSO Firefly/Renilla ratios as positive andnegative controls, respectively.

Table 3 shows EC_(k) data for representative compounds (Cpd #) tested inthe Primary Assay and Table 4 shows the max efficacy (E_(max), %) forrepresentative compounds (Cpd #) tested in the Primary Assay.

TABLE 3 Cpd # EC_(k) (μM)  (5) 63.50  (15) 157.90  (25) 9.35  (28)122.85  (32) 60.00  (34) 26.60  (37) 36.50  (48) 72.75  (49) 42.50  (55)1.71  (56) 8.23  (57) 31.20  (58) 17.95  (73) 17.05  (77) 1-10(RT-PCR)^(b)  (81) 3.08  (84) 1-10 (RT-PCR)ª  (90) 11.85  (94)  10-31.6(RT-PCR)ª  (95) 121.65 (100) 2.18 (104) 12.02 (105) 10.36/ Fireflyonly^(c) (107) 4.58/ Firefly only^(c) (109) 12.16/ Firefly only^(c)(110) 4.92/ Firefly only^(c) (111) 9.3/ Firefly only^(c) (112) 5.33/Firefly only^(c) (113) 5.17 (114) 6.59/ Firefly only^(c) (115) 5.92(116) 31.80 (118) 10.50 (119) 11.20 (120) 2.75 (121) 17.30 (122) 5.65(123) 4.90 (124) 2.41 (125) 6.52 (126) 4.73 (127) 5.45 (128) 15.45 (129)5.60 (130) 8.90 (131) 7.00 (133) 11.81 (134) 6.25 (135) 9.06 (136) 7.52(137) 7.25 (138) 12.75 (142) 16.10 (144) 7.70 (146) 9.41 (150) 1-10(RT-PCR)ª (154) 22.25 (155) 22.25ª (156) 15.80 (158) 13.40 (159) 1-10(RT-PCR)ª (162) 48.70 (170) 49.55 (181) 8.40 (184) 3.62 (188) 11.70(191) 5.92 (192) 7.13 (194) 4.49 (198) 5.01 (202) 9.35 (205) 6.41 (207)75.80 (208) 107.00 (209) 12.20 (210) 69.20 (211) 7.73 (214) 11.25 (217)7.07 (218) 21.00 (220) 8.62 (222) 8.99 (224) 9.49 (225) 21.05 (226) 1.80(227) 23.30 (228) 15.65 (230) 1.50 (233) 1.59 (234) 19.90 (238) 64.80(239) 2.60 (240) 18.25 (243) 17.00 (244) 7.05 (245) 15.45 (247) 5.41(249) 0.72 (250) 62.80 (251) 3.65 (253) 11.85 (254) 13.20 (256) 17.35(258) 15.75 (259) 0.38 (260) 3.43 (261) 2.62 (262) 28.45 (263) 27.40(265) 7.33 (266) 8.52 (267) 2.40 (269) 1.39 (270) 0.59 (271) 0.29 (272)2.60 (273) 0.62 (274) 0.42 (275) 0.75 (276) 1.13 (277) 0.46 (278) 6.37(282) 0.42 (285) 6.78 (287) 7.56 (289) 0.87 (290) 2.04 (291) 3.47 (292)0.24 (293) 1.78 (294) 0.44 (296) 1.81 (297) 4.09 (299) 1.30 (300) 10.00(302) 1.42 (303) 1.51 (304) 4.14 (305) 0.43 (306) 0.70 (307) 0.21 (308)0.15 (309) 2.08 (310) 1.50 (311) 0.56 (312) 2.29 (313) 7.48 (314) 2.31(315) 2.52 (316) 7.09 (317) 0.16 (318) 0.54 (319) 1.56 (320) 0.52 (321)1.41 (324) 0.16 (326) 0.07 (327) 4.64 (328) 1.79 (329) 1.97 (331) 0.69(332) 0.78 (334) 0.87 (338) 1.10 (339) 1.31 (340) 0.95 (341) 4.16 (346)1.42 (347) 0.77 (348) 0.70 (349) 0.29 (362) 0.22 (372) 3.71 (375) 2.18(377) 7.21 (380) 4.38 (382) 1.31 (384) 1.08 (387) 0.33 (388) 0.68 (389)0.73 (390) 0.74 (391) 1.02 (392) 1.9 (393) 7.4 (395) 1.8 (398) 0.94(466) 3.66 (471) 1.63 (472) 1.16 (473) 2.1 (475) 3.16 (477) 2.28 (479)3.23 (480) 1.17 (481) 4.14 (482) 11.12 (483) 1.26 (486) 2.57 (487) 6.1(488) 1.02 (489) 1.21 (490) 0.62 (491) 0.48 (493) 3.05 (496) 1.03 (497)5.56 (499) 1.67 (500) 3 (505) 8.07 (506) 1.14 (507) 0.77 ^(a)Fireflyinhibitor ^(b)Renilla interference ^(c)Renilla interference/Firefly only

TABLE 4 Cpd # E_(max) (%)  (1)  19  (3)  59  (6)  21  (7)  39  (8)  25 (10)  21  (12)  54^(a)  (13)  16  (14)  53  (16)  67  (18)  39  (20) 22  (22)  49  (23)  34  (26)  66  (28)  98  (36)  18  (38)  5  (41)  35 (44)  19  (45)  56  (47)  99  (54)  13  (55) 173  (56) 152  (58) 155 (60)  13  (65)  32  (67)  13  (68)  62  (72)  39  (73) 133  (74)  64 (76)  69  (77) 321 (RT-PCR)^(b)  (79)  43  (83)  4  (84) 250.6(RT-PCR)^(a)  (85)  96  (86)  29  (87)  46  (88)  33  (89)  21  (90) 159 (93)  63  (94) 180.1 (RT-PCR)^(a)  (95) 103  (96)  65  (99)  47 (100)235 (102)  52 (104) 246 (105) 134.5/Firefly only^(c) (106)  14 (107)183.5/Firefly only^(c) (108) 172 (RT-PCR)^(a) (109) 128/Firefly only^(c)(110) 193/Firefly only^(c) (111) 191/Firefly only^(c) (112)110.85/Firefly only^(c) (113) 132 (114) 174/Firefly only^(c) (115) 174(116) 112 (117)  23 (118) 112 (119) 114 (120) 166 (121) 189 (122) 256(123)  92 (124) 180 (125) 225 (126) 155 (127) 264 (128) 155 (129) 169(130) 201 (131) 190 (132)  67.7 (RT-PCR)^(a) (133) 143 (134) 174 (135)194 (136) 143 (137) 214 (138) 174 (139)  52.2 (RT-PCR)^(a) (141) 103(142) 121 (143)  24 (144) 127 (145)  59 (146) 154 (147)  80 (148)  62(150) 320 (RT-PCR)^(a) (151)  73 (152)  35 (153)  20 (154) 151 (155)151^(a) (156)  73 (158)  20 (159) 228^(a) (160)  85 (161)  65 (162) 103(163)  35 (164)  68 (165)  59 (166)  80 (167)  37 (168)  54 (170)  92(171)  48 (172)  61 (173)  30 (174)  37 (175)  29 (176)  48 (177)  60(178)  76 (179)  49 (180)  28 (181) 122 (182)  20 (184) 169 (185)  22(186)  17 (187) 111 (188) 145 (189)  33 (190)  68 (191) 231 (192) 210(194) 241 (195)  81 (196)  7 (197)  14 (198) 125 (199)  22 (200)  11(201)  27 (202) 137 (203)  27.00^(a) (204)  27 (205)  27 (206)  27 (207)109 (208)  83 (209) 176 (210) 104 (211) 204 (212)  71 (213)  36 (214)197 (216)  16 (217) 151 (218) 154 (220) 153 (221)  86 (222) 146 (223) 95 (224) 139 (225) 114 (226) 191 (227) 163 (228) 152 (229)  55 (230)216 (231)  77 (232)  59 (233) 152 (234)  94 (235)  80 (236)  83 (237) 21 (238)  64 (239) 147 (240) 124 (241)  13 (242)  31 (243) 120 (244)150 (245) 122 (246)  22 (247) 215 (248)  10 (249) 256 (250)  63 (251)258 (252)  43 (253) 187 (254) 145 (255)  42 (256) 129 (257)  62 (258)165 (259) 109 (260) 130 (261) 143 (262)  64 (263) 105 (264)  44 (265)119 (266) 106 (267) 183 (268)  19 (269) 119 (270) 218 (271) 206 (272)155 (273) 254 (274) 259 (275) 230 (276) 188 (277) 197 (278) 141 (279) 54 (280)  25 (281)  17 (282) 233 (283)  29 (284)  27 (285) 115 (286) 38 (287) 106 (288)  56 (289) 128 (290) 238 (291) 165 (292) 312 (293)169 (294) 183 (295)  54 (296) 178 (297) 150 (298)  21 (299) 216 (300) 84 (301)  45 (302) 176 (303) 243 (304) 166 (305) 284 (306) 247 (307)292 (308) 310 (309) 194 (310) 191 (311) 221 (312) 195 (313) 102 (314)198 (315) 165 (316) 108 (317) 223 (318) 186 (319) 204 (320) 208 (321)197 (322)  21 (323)  26 (324) 226 (325)  20 (326) 287 (327) 145 (328)184 (329) 209 (330)  20 (331) 209 (332) 189 (333)  51 (334) 177 (335) 35 (336)  20 (337)  23 (338) 222 (339) 188 (340) 220 (341) 155 (342) 16 (344)  18.35 (346) 181 (347) 186.5 (348) 171 (349) 227 (350)  49.5(351)  22 (352)  25 (353)  78 (354)  57.5 (355)  26 (356)  17 (359) 31.5 (360)  12.3 (361)  9.8 (362) 250 (363)  53.2 (364)  18.2 (365) 22.4 (366)  19.2 (367)  94 (368)  2.4 (369)  57.8 (370)  33 (371)  82(372) 125.5 (373)  25.1 (374)  34.2 (375) 133.5 (376)  23.5 (377) 101.3(378)  31.8 (379)  95 (380) 108 (381)  63.4 (382) 192.7 (383)  30.3(384) 151.5 (385)  46 (386)  69.2 (387) 238.4 (388) 215.3 (389) 211(390) 201 (391) 193.2 (392) 134.5 (393)  85.2 (394)  4.8 (395) 180.5(396)  38.7 (397)  26.3 (398) 176 (400)  11.4 (401)  41.2 (402)  21(403)  39 (404)  51 (406)  20 (411)  55 (415)  10.9 (426)  59 (438)  44(441)  42.8 (442)  58.6 (456)  52.3 (458)  73.1 (463)  90 (465) 26.3/RT-PCR^(a) (466) 221 (469)  13.3 (470)  76.8 (471) 149 (472) 151(473) 130.2 (474)  24.9 (475) 136.5 (476)  25.5 (477) 107.5 (478)  84.1(479) 143.5 (480) 155.5 (481)  93.4 (482)  99.1 (483) 138 (484)  40.2(485)  72.3 (486) 150.5 (487) 114.2 (488) 206.5 (489) 131 (490) 176.5(491) 155 (492)  54.5 (493) 168 (494)  14.1 (495)  13.9 (496) 233 (497)120.5 (498)  37.7 (499) 156.5 (500) 141 (501)  18.1 (502)  28 (503) 27.2 (504)  80 (505) 139.5 (506) 144.5 (507) 167 (508)  80 (509)  40.8(510)  20 (511)  35.15 (512)  43.7 ^(a)Firefly inhibitor ^(b)Renillainterference ^(c)Renilla interference/Firefly only

Example 45. Secondary Assay

Compounds with an EC_(k)<2 μM in the primary assay (see Example 44) wereused in a secondary assay to treat FD fibroblast. The splicing analysisof IKBKAP in the FD fibroblast was used to validate the results of themost potent compounds obtained with the primary assay in vitro. FDfibroblasts GM04663 were purchased from the Coriell Cell Repository andwere grown in Dulbecco's Modified Eagle's media (DMEM) (GIBCO ref11995-065). The media was supplemented with 2 mM L-glutamine, 100penicillin/streptomycin and 10% fetal bovine serum (SIGMA cat. 12306C).Cells were plated in 6-wells and were treated 24 hours after plating.Compounds are added to the media using two different concentrations(0.08 μM and 0.8 μM). Cells were also treated with Kinetin 200 μM andDMSO 0.50%. Test compounds and kinetin were diluted in PBS with a finalDMSO concentration of 0.5%. After 24 hours of treatment total RNA was aextracted using QIAzol (QUIAGEN cat. 79306) following the manufacture'sprotocol. Reverse Transcription (RT) was then performed using 0.5 μg oftotal RNA, oligo(dT), random primers, and Superscript III (INVITROGENcat. 18080-044) reverse transcriptase according to manufacturer'sprotocol. For splicing assessment, semi-quantitave PCR was used withcDNA equivalents of 75 ng of starting RNA in a 20 μL reaction mixture,with the use of Go Taq Green Master Mix (PROMEGA ref. M712C) andspecific primers that recognize exon 19 (EXON19F: CCT GAG CAG CAA TCATGT G; SEQ ID NO:1) and exon23 (EXON23R: TAC ATG GTC TTC GTG ACA TC; SEQID NO:2) of IKBKAP. The PCR reaction was a carried out for 35 cycles(94° C. for 30 seconds; 58° C. for 30 seconds; 72° C. for 30 seconds) ina C1000 ThermoCycler (BIORAD). The PCR products were separated in a 1.5%agarose (INVITROGEN ref. 16500) gel stained with Ethidium Bromide (SIGMAE1501). The bands were visualized with UV light using the AlphaImager2200 (ALPHA INNOTECH). IKBKAP wild type band is 363 base pairs (bp) andIKBKAP mutant band is 289 bp due to exon20 skipping. Relative bandintensity was determined by evaluating the integrated density values asdetermined by ImageJ software. Splicing correction was measured as theratio of wild type transcript to total transcript (mutant plus wildtype). These values were normalized using the splicing correction valuesof Kinetin and DMSO treated samples as positive and negative controls.The results were used to confirm the data obtained with the primaryassay and to discriminate compounds based on their potency in vitro.

Table 5 shows % exon inclusion data (normalized) for representativecompounds at various concentrations (μM) using the secondary assay.

TABLE 5 % exon Compound Concentration Inclusion Standard No. (μM)Normalized Deviation Kinetin 200 100 8.20 (271) 0.08 62.17 15.10 (271)0.8 106.66 8.20 (274) 0.08 37.94 7.70 (274) 0.8 99.03 10.50 (320) 0.0847.12 3.00 (320) 0.8 103.47 7.60 (302) 0.08 23.29 7.40 (302) 0.8 90.809.00 (319) 0.08 14.24 6.00 (319) 0.8 77.85 9.00 (347) 0.8 72.01 9.74(347) 0.08 18.31 9.18 (346) 0.8 58.64 13.06 (346) 0.08 23.20 11.06 (100)0.8 62.10 17.72 (100) 0.08 22.62 6.28 (348) 0.8 101.72 8.19 (348) 0.0849.042 6.44 (349) 0.8 95.28 7.51 (349) 0.08 27.07 5.13 (362) 0.8 104.6923.98 (362) 0.08 63.75 24.64 Kinetin 200 100 3.66 (275) 0.08 37.19 2.34(275) 0.8 101.23 3.18 (269) 0.08 34.84 5.76 (269) 0.8 101.51 3.18 (230)0.08 22.27 5.26 (230) 0.8 69.99 2.72 (270) 0.08 28.70 10.17 (270) 0.8101.36 3.46 (372) 0.08 13.41 4.12 (372) 0.8 48.69 9.13 (107) 0.8 93.243.63 (107) 0.08 25.64 2.46 (285) 0.8 1.46 6.05 (285) 0.08 0.06 2.37

Example 46. In Vivo Familial Dysautonomia Mouse Model Compound (100)

Compound (100) was administered by oral gavage for eight days at 60mg/kg/day, 30 mg/kg/day and 10 mg/kg/day to the mouse transgenicfamilial dysautonomia (FD) model. Every dosing group and the controlgroup (vehicle) consisted of 6 mice. The mice were given food and waterad libitum, and changes in body weights were monitored on a daily basis.On the eighth day the mice were dosed for the last time and after 1 hourthe mice were sacrificed and dissected. Plasma, liver, kidney, heart andbrain were collected. The splicing analysis was performed in all tissuesand confirmed the presence of (100) in the plasma. Compound (100)improved splicing in kidney, heart, and liver at all doses tested(doses=10, 30 and 60 mg/kg/day). In liver, compound (100) at 30mg/kg/day reached the same level of correction observed with Kinetintreatment at 400 mg/kg/day. In heart, compound (100) at 10 mg/kg/dayimproved splicing better than Kinetin at 400 mg/kg/day. In kidney, therewere no significant changes in splicing after treatment with kinetin at400 mg/kg/day whereas improvements were observed using compound (100)even at 10 mg/kg/day. Compound (100) was evident in the brain andcorrected splicing at 30 and 60 mg/kg whereas there was no significantchange observed in the brain after 8 days of treatment with kinetin 400mg/kg/day.

In liver, it was shown that the treatment with compound (100) at 30mg/kg/day increased the level of the IKAP protein whereas there were nosignificant changes after treatment with kinetin at 400 mg/kg/day.

Compounds (230) and (270)

The following solutions were prepared daily: Compound (230) in 10%DMA/45% PEG 300/12% EtOH/33% sterile water; and Compound (270) in 10%DMA/45% PEG 300/12% EtOH/33% sterile water.

Six transgenic mice for each dose (60, mg/kg/day; 30 mg/kg/day; and 10mg/kg/day) were fed using a 20 Gauge feeding needle (Fine Science ToolsInc., CA, USA) for a period of 8 days. Six transgenic mice were feddaily with 10% DMA/45% PEG 300/12% EtOH/33% sterile water solution forthe same duration. The mice were given food and water ad libitum, andchanges in body weights were monitored on a daily basis. On the eighthday the mice were dosed for the last time and after 1 hour weresacrificed and dissected. Plasma, lungs, muscle, liver, heart, brain,kidney, sciatic nerve, and trigeminal nerve were collected. Splicing wasevaluating by RT-PCT and IKAP protein was evaluated using WesternBlotting.

Results

The data shown in FIGS. 1A-6 for representative compounds (100), (230)and (270) demonstrate that the compounds are useful for improvinginclusion of exon 20.

Example 47. Protein Isolation and Western Blot Analysis

Protein extracts were obtained by homogenizing liver or cell pellets inRIPA buffer (Tris-HCl 50 mM, pH 7.4; NaCl 150 mM; NP-40 1%; Sodiumdeoxycholate 0.5%; SDS 0.1%) containing protease inhibitor cocktail(Sigma), DTT (100 μM) and PMSF (100 μM). Insoluble debris were discardedafter centrifugation and protein concentration was determined usingPierce® 400 BCA Protein Assay Kit (Thermo Scientific). 50 μg of proteinwas separated on NuPage 4-12% Bis-Tris Gel (Invitrogen) and transferredinto nitrocellulose membrane (Thermo Scientific). Membrane was blockedin 5% non-fat milk for one hour at room temperature and incubatedovernight at 4° C. with rabbit polyclonal antibody against theC-terminus region of the human IKAP protein (Anaspec, 1:2000) or mousemonoclonal antibody against human IKAP protein (Sigma, 1:2000) and withthe rabbit polyclonal antibody against actin (Sigma, 1:2000).

Membranes were washed and incubated with secondary antibodies for 1 hourat room temperature. Protein bands were visualized by chemiluminescence(Pierce® 407 ECL Western 408 Blotting Substrate, Thermo Scientific)followed by exposure to autoradiographic film. IKAP levels in FDfibroblasts were compared with the level of protein found inheterozygote (HET) fibroblasts, as shown in FIG. 7 .

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

1-70. (canceled)
 71. A compound of Formula (Ir):

or a pharmaceutically acceptable salt thereof, wherein: L is absent orselected from the group consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene,and C₂₋₆ alkynylene, wherein the C₁₋₆ alkylene, C₂₋₆ alkenylene, andC₂₋₆ alkynylene are each optionally substituted by 1, 2, 3, or 4independently selected R²⁰ groups; R¹ is selected from the groupconsisting of a C₆₋₁₀ aryl, 2-benzofuranyl, 4-quinolinyl, a 5-6 memberheteroaryl, and a 5-6 member heterocycloalkyl, each optionallysubstituted by 1, 2, 3, or 4 independently selected R^(1A) groups; eachR^(1A) is independently selected from halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, —C(═O)OH, —C(═O)C₁₋₆alkyl, —C(═O)C₁₋₆ haloalkyl, and —C(═O)C₁₋₆ alkoxy; R² is selected fromthe group consisting of H, oxo, azido, halo, CN, NO₂, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, 4-10 membered heterocycloalkyl, OR^(a2), C(═O)R^(b2),C(═O)OR^(b2), NR^(c2)R^(d2), C(═O)NR^(c2)R^(d2), —OC(═O)NR^(c2)R^(d2),NR^(c2)C(═O)R^(b2), NR^(c2)C(═O)OR^(b2), N^(c2)C(═O)NR^(c2)R^(d2),NR^(c2)S(═O)₂R^(b2), NR^(c2)S(═O)₂NR^(c2)R^(d2), S(O)NR^(c2)R^(d2), andS(O)₂NR^(c2)R^(d2), wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl areeach optionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups; R³ is selected from the group consisting of H, oxo, azido, halo,CN, NO₂, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR^(a3),SR^(a3), C(═O)R^(b3), C(═O)OR^(b3), NR^(c3)R^(d3), C(═O)NR^(c3)R^(d3),—OC(═O)NR^(c3)R^(d3), NR^(c3)C(═O)R^(b3), NR^(c3)C(═O)OR^(b3),NR^(c3)C(═O)NR^(c3)R^(d3), NR^(c3)S(═O)₂R^(b3),NR^(c3)S(═O)₂NR^(c3)R^(d3), S(O)NR^(c3)R^(d3), and S(O)₂NR^(c3)R^(d3),wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl are each optionallysubstituted by 1, 2, 3, or 4 independently selected R²⁰ groups; R⁵ isselected from the group consisting of H, oxo, azido, halo, CN, NO₂, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, 4-10 membered heterocycloalkyl, OR^(a5), SR^(a5),C(═O)R^(b5), C(═O)OR^(b5), NR^(c5)R^(d5), C(═O)NR^(c5)R^(d5),—OC(═O)NR^(c5)R^(d5), NR^(c5)C(═O)R^(b5), NR^(c5)C(═O)OR^(b5),NR^(c5)C(═O)NR^(c5)R^(d5) NR^(c5)S(═O)₂R^(b5),NR^(c5)S(═O)₂NR^(c5)R^(d5), S(O)NR^(c5)R^(d5), and S(O)₂NR^(c5)R^(d5),wherein the C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10 memberedheteroaryl, and 4-10 membered heterocycloalkyl are each optionallysubstituted by 1, 2, 3, or 4 independently selected R²⁰ groups; R⁶ isselected from the group consisting of H, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₆ hydroxyalkyl, and C₁₋₆ alkoxy; each R^(a2), R^(b2), R^(c2), R^(d2),R^(a3), R^(b3), R^(c3), R^(d3), R^(a5), R^(b5), R^(c5), and R^(d5) isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ hydroxyalkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy,—(C₁₋₆ alkylene)-C₁₋₆ alkoxy, C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, 5-10 membered heteroaryl, 4-10 memberedheterocycloalkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₁₀ cycloalkyl, —(C₁₋₆ alkylene)-C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5-10membered heteroaryl, and 4-10 membered heterocycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups; or R^(c2) and R^(d2) together with the N atom to which they areconnected, come together to form a 5-10 membered heteroaryl or 4-10membered heterocycloalkyl ring, each optionally substituted by 1, 2, 3,or 4 independently selected R²⁰ groups; or R^(c3) and R^(d3) togetherwith the N atom to which they are connected, come together to form a5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, eachoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups; and each R²⁰ is independently selected from the group consistingof OH, SH, CN, NO₂, halo, oxo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,C₁₋₄ haloalkyl, C₁₋₄ cyanoalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ alkoxy, —(C₁₋₄alkyl)-(C₁₋₄ alkoxy), —(C₁₋₄ alkoxy)-(C₁₋₄ alkoxy), C₁₋₄ haloalkoxy,C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 memberedheterocycloalkyl, amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, carbamyl,C₁₋₄ alkylcarbamyl, di(C₁₋₄ alkyl)carbamyl, carbamoyl, C₁₋₄alkylcarbamoyl, di(C₁₋₄ alkyl)carbamoyl, C₁₋₄ alkylcarbonyl, C₁₋₄alkoxycarbonyl, C₁₋₄ alkylcarbonylamino, C₁₋₄ alkylsulfonylamino,aminosulfonyl, C₁₋₄ alkylaminosulfonyl, di(C₁₋₄ alkyl)aminosulfonyl,aminosulfonylamino, C₁₋₄ alkylaminosulfonylamino, di(C₁₋₄alkyl)aminosulfonylamino, aminocarbonylamino, C₁₋₄alkylaminocarbonylamino, and di(C₁₋₄ alkyl)aminocarbonylamino.
 72. Thecompound of claim 71, wherein L is C₁₋₆ alkylene optionally substitutedby 1, 2, 3, or 4 independently selected R²⁰ groups.
 73. The compound ofclaim 71, wherein L is unsubstituted methylene or unsubstitutedethylene.
 74. The compound of claim 71, wherein R¹ is selected from thegroup consisting of 2-benzofuranyl, 4-quinolinyl, phenyl, 5-6 memberedheteroaryl, and 5-6 membered heterocycloalkyl, each optionallysubstituted by 1 or 2 independently selected R^(1A) groups.
 75. Thecompound of claim 71, wherein R¹ is selected from the group consistingof:


76. The compound of claim 71, wherein each R^(1A) is independentlyselected from the group consisting of halo, CN, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ alkoxy, and —C(═O)OH.
 77. The compound of claim 71,wherein each R^(1A) is independently selected from the group consistingof CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, and —C(═O)OH.78. The compound of claim 71, wherein R² is selected from the groupconsisting of H, oxo, halo, CN, C₁₋₆ alkyl, OR^(a2), NR^(c2)R^(d2), 5-6membered heteroaryl, 5-6 membered heterocycloalkyl, C(═O)OR^(a2), andC(═O)NR^(c2)R^(d2), wherein the C₁₋₆ alkyl and 4-10 memberedheterocycloalkyl are each optionally substituted by 1, 2, 3, or 4independently selected R²⁰ groups.
 79. The compound of claim 71, whereinR³ is selected from the group consisting of H, oxo, azido, CN, C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 memberedheterocycloalkyl, OR^(a3), SR^(a3), NR^(c3)R^(d3), C(═O)OR^(a3),—C(═O)NR^(c3)R^(d3), —OC(═O)R^(b3), wherein the C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, 5-6 membered heteroaryl, and 5-6 memberedheterocycloalkyl, are each optionally substituted by 1, 2, 3, or 4independently selected R²⁰ groups.
 80. The compound of claim 71, whereinR³ is selected from the group consisting of H, azido, CN, methyl,cyclopropyl, cyclobutyl, phenyl, 3-pyridinyl, N-morpholino, methoxy,ethoxy, n-propoxy, isopropoxy, n-butoxy, —OCH₂CH₂OH, —OCH₂CH₂CH₂OH,—OCH₂CH₂OCH₃, —OCH₂CH₂CH₂OCH₃, —ONHCH₃, —OCH₂CHF₂, —OCH₂CF₃,—OCH₂CH₂CF₃, —OCH₂CHF₂CH₃, —OCH₂CH₂NHC(═O)CH₃, cyclobutoxy,—OCH₂CH₂—O-phenyl, —SCH₃, —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—NHCH₂CH₂CH₂OH, —CH₂OCH₃, —CH₂OH, —CH₂NHCH₃, —CH₂N(CH₃)₂, —C(═O)OCH₃,—C(═O)NH₂, —C(═O)NHCH₃, —C(═O)N(CH₃)₂, —NHCH₂CH₂OH, —C(═O)NHCH₂CH₂OH,—OC(═O)CH₃, —OCH₂-azetidinyl, —OCH₂-oxetanyl,


81. The compound of claim 71, wherein R⁵ is selected from the groupconsisting of H, halo, CN, C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5),NR^(c5)R^(d5), C₃₋₆ cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl.82. The compound of claim 71, wherein R⁵ is selected from the groupconsisting of H, fluoro, chloro, bromo, iodo, CN, methyl, isopropyl, OH,OCH₃, NH₂, —NHCH₃, —N(CH₃)₂, —SCH₃, phenyl, cyclopropyl, and


83. The compound of claim 71, wherein R⁵ is chloro or fluoro.
 84. Thecompound of claim 71, wherein R⁶ is H or C₁₋₆ alkyl.
 85. The compound ofclaim 71, wherein: L is unsubstituted C₁₋₆ alkylene; R¹ is selected fromthe group consisting of 2-benzofuranyl, 4-quinolinyl, C₆₋₁₀ aryl, 5-6membered heteroaryl, 5-6 membered heterocycloalkyl, optionallysubstituted by 1, 2, 3, or 4 independently selected R^(1A) groups; eachR^(1A) is independently selected from the group consisting of halo, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ alkoxy, and —C(═O)OH; R² is selectedfrom the group consisting of H, oxo, halo, CN, C₁₋₆ alkyl, OR^(a2),NR^(c2)R^(d2), 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl,C(═O)OR^(a2), and C(═O)NR^(c2)R^(d2), wherein the C₁₋₆ alkyl and 4-10membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or4 independently selected R²⁰ groups; R³ is selected from the groupconsisting of H, oxo, azido, CN, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl,5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, OR^(a3),SR^(a3), NR^(c3)R^(d3), C(═O)OR^(a3), —C(═O)NR^(c3)R^(d3),—OC(═O)R^(b3), wherein the C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, 5-6membered heteroaryl, 5-6 membered heterocycloalkyl, are each optionallysubstituted by 1, 2, 3, or 4 independently selected R²⁰ groups; R⁴ isselected from the group consisting of H, oxo, azido, halo, CN, C₁₋₆alkyl, OR^(a4), NR^(c4)R^(d4), and 4-10 membered heterocycloalkyl,wherein the C₁₋₆ alkyl and 4-10 membered heterocycloalkyl are eachoptionally substituted by 1, 2, 3, or 4 independently selected R²⁰groups; and R⁵ is selected from the group consisting of H, halo, CN,C₁₋₆ alkyl, C₁₋₆ haloalkyl, OR^(a5), SR^(a5), NR^(c5)R^(d5), C₃₋₆cycloalkyl, C₆₋₁₀ aryl, and 5-6 membered heteroaryl.
 86. The compound ofclaim 71, wherein: L is unsubstituted methylene or unsubstitutedethylene; R¹ is selected from the group consisting of unsubstituted2-furanyl, unsubstituted 4-quinolinyl, and unsubstituted phenyl; R⁵ ishalo; and R⁶ is H.
 87. The compound of claim 86, wherein: L isunsubstituted methylene; and R¹ is unsubstituted 2-furanyl.
 88. Thecompound of claim 71, wherein the compound of Formula (Ir) has formula:

or a pharmaceutically acceptable salt thereof.
 89. A pharmaceuticalcomposition comprising a compound of claim 71, or a pharmaceuticallyacceptable salt thereof, and at least one pharmaceutically acceptablecarrier.
 90. A method of reducing or alleviating one or more symptoms offamilial dysautonomia, the method comprising administering to a subjectin need thereof a therapeutically effective amount of a compound ofclaim 71, or a pharmaceutically acceptable salt thereof.